Review Article | Open Access
Chenglin Han, Zilong Wang, Yingkun Xu, Shuxiao Chen, Yuqing Han, Lin Li, Muwen Wang, Xunbo Jin, "Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer", BioMed Research International, vol. 2020, Article ID 1269624, 19 pages, 2020. https://doi.org/10.1155/2020/1269624
Roles of Reactive Oxygen Species in Biological Behaviors of Prostate Cancer
Prostate cancer (PCa), known as a heterogenous disease, has a high incidence and mortality rate around the world and seriously threatens public health. As an inevitable by-product of cellular metabolism, reactive oxygen species (ROS) exhibit beneficial effects by regulating signaling cascades and homeostasis. More and more evidence highlights that PCa is closely associated with age, and high levels of ROS are driven through activation of several signaling pathways with age, which facilitate the initiation, development, and progression of PCa. Nevertheless, excessive amounts of ROS result in harmful effects, such as genotoxicity and cell death. On the other hand, PCa cells adaptively upregulate antioxidant genes to detoxify from ROS, suggesting that a subtle balance of intracellular ROS levels is required for cancer cell functions. The current review discusses the generation and biological roles of ROS in PCa and provides new strategies based on the regulation of ROS for the treatment of PCa.
PCa has the highest prevalence for males in Europe as well as America and is also the second leading cause of cancer-related deaths for males . In the year 2020, approximately 1,920,000 new cases of PCa are expected to be diagnosed, of which 33,000 may die . The incidence of PCa has increased in recent years, notably in developing countries, which is strongly associated with economic development and lifestyle [2–5]. Multiple processes are involved in malignant transformation of prostate cells, initiating as prostatic intraepithelial neoplasia (PIN) followed by localized PCa. The early stages of PCa progression are treated by radical prostatectomy and localized radiation . Once these therapies fail, the standard treatment for late-stage PCa is aimed at preventing androgen binding to AR (androgen deprivation therapy, ADT) or inhibiting AR activity directly (antiandrogens). This strategy comes from the fact that the primary prostate tumor is mostly made up of Androgen Receptor-positive (AR+) cancer cells, which are initially androgen-dependent. Despite responding to ATD during the first 14-20 months, almost all patients acquire resistance and progress into castration-resistant prostate cancer (CRPC) with primary metastasis of the lymph nodes or bones ; it is often fatal, and the overall survival (OS) is relatively low. Therefore, the treatment of PCa remains a formidable challenge and enigma.
ROS are a class of highly reactive, oxygen-containing molecules mainly including superoxide anion, hydrogen peroxide, hydroxyl radicals, and singlet oxygen , which cannot be detected directly in human specimens due to their short half-lives . Hydroxyl radical (OH-) is the most unstable and reacts fleetly with adjacent biomolecules. Additionally, hydrogen peroxide (H2O2), as the major species of ROS, can cross the cell membranes and exert effects beyond the cell limits . Intracellular ROS levels are tightly dependent on the various synthesis and degradation pathways. Maintenance of ROS at physiological levels is crucial to redox regulation involving repair, survival, and differentiation [7, 10]. However, either excessive generation of ROS or a decrease in the free radical scavenging system may increase ROS levels, thus inducing oxidative stress that acts as an etiological factor for wide varieties of pathologies, such as diabetes, myocardial injury, and cancer [4, 10]. As two-faced molecules, ROS have either beneficial or deleterious effects on PCa cells. Many experimental and clinical results have demonstrated that higher levels of ROS, particularly free radicals, can cause oxidative damages in DNA, proteins, and lipids, further contributing to the pathogenesis and the progression of PCa [11, 12]. Thus, it is reasonable to anticipate that the use of antioxidants has the potential to prevent and treat prostate carcinogenesis by eliminating ROS and oxidative stress. Besides, further accumulation of ROS could disturb normal cellular processes, eventually resulting in cell death [13, 14].
This current review aims to focus on proposed mechanisms by which ROS either promote or inhibit the progression of PCa and provides clues for anticancer therapies based on redox regulation. With respect to the extensive pleiotropy of ROS, the emerging field of redox medicine has received increasing attention in recent years. Therefore, further studies are required to elucidate the relationship between ROS and PCa.
2. Sources of Intracellular ROS in PCa
Both endogenous and exogenous sources promote the generation of intracellular ROS. Higher levels of basal ROS in PCa cells result from mitochondria dysfunction, increased p66Shc, glucose metabolism (Warburg effect), and the activation of enzymes including NADPH oxidases, xanthine oxidases, and cytochrome P450 . In the following paragraphs, we especially pay attention to mitochondria dysfunction, NADPH oxidases, and p66Shc activation, which are significant contributors of endogenous ROS in PCa . On the other hand, ROS generation is also driven in response to extracellular stimuli, such as hypoxia, growth factors, androgen, and inflammation (Figure 1). Growth factors activate the small RhoGTPase K-ras downstream to elevate intracellular superoxide levels through mitochondria or NADPH oxidases .
2.1. Mitochondria Dysfunction
Mitochondrial electron transport chain (ETC) composed of complex I, III, and IV induces oxidative phosphorylation (OXPHOS) to produce ATP with a by-product ROS generation due to inevitable electron leakage to O2, which is identified as the major endogenous source of ROS . It is well documented that mitochondrial DNA (mtDNA), double-stranded circular DNA, is resident in the mitochondrial matrix encased within a double-membrane system composed of the outer and inner mitochondrial membrane. MtDNA contains 37 genes, of which 13 protein components are involved in OXPHOS [19, 20]. It has been reported that mtDNA mutations, including an overall reduction and increased variability of contents in PCa cells, would deteriorate OXPHOS, thus increasing the production of ROS [21–23]. Previous research reported that approximately 11–12 percentages of PCa patients manifested mutational cytochrome oxidase subunit I (COI) with significant functions . Additionally, high levels of mitochondrial complex I-encoding genes mutation of PCa decrease 70% NADH-pathway capacity and increase ROS levels, particularly in high-grade PCa . Remarkably, prostate tumors implanted subcutaneously with the pathogenic mtDNA ATP6 T8993G mutation of the PC3 cells were seven times larger than the wild-type (T8993T) cybrids; the mutant tumors also generated significantly more ROS . Furthermore, ROS can attack polyunsaturated fatty acids in membranes to trigger mtDNA leakage . Lack of histone protein protection and damage-repair mechanisms, the exposed mtDNA is prone to mutations induced by ROS, which is called ROS-induced ROS-release and causes a vicious cycle .
2.2. NADHP Oxidases (NOXs)
NOX is a complex membrane protein consisting of the catalytic subunits gp91phox, p22phox, regulatory subunits p40phox, p47phox, p67phox, and the small GTPase Rac [29, 30]. The NOX family comprises seven isoforms: NOX 1–5 and dual oxidases (DUOX) 1 and 2 . NOXs catalyze the transfer of electron across biological membranes via electron donor NADPH and are responsible for ROS generation, which includes both superoxide and hydrogen peroxide [32, 33]. NOX1, NOX2, NOX4, and NOX5 expressions are increased explicitly in a high percentage of PCa cells compared to benign cell lines, consequently contributing to PCa survival and progression via ROS-regulated signaling cascades [34, 35]. ROS produced by NOX4 mediate the antiapoptotic effect of growth factors . Although having similar structures, the NOXs are activated by specific mechanisms and regulatory subunits, respectively . Especially, as NOX2 and NOX4 mRNAs are androgen-dependently regulated, radiotherapy has shown a significant benefit in metastasis-free survival when used in combination with ADT at early stages . These findings collectively suggest that exploring specific antisense targeting of NOX enzymes or NOX enzyme inhibitors may represent a valuable strategy for PCa treatment by modulating the NOX-dependent intracellular redox status.
p66shc, a prooxidant isoform of the ShcA adaptor protein family, has the same modular structure of p52Shc/p46Shc (SH2-CH1-PTB) and an additional N-terminal CH2 domain containing a particular phosphorylated serine residue at position 36 (Ser36) [39, 40]. Oxidative stress induces ser36 phosphorylation to trigger p66Shc activation, which, in turn, promotes electron transfer from cytochrome c to oxygen, thereby increasing the generation of hydrogen peroxide [41, 42]. p66shc also leads to ROS generation by increasing NOXs levels or impairing intracellular antioxidant levels indirectly through inhibiting the activities of FOXO transcription factors . Clinical prostate tumors show higher levels of p66Shc, relative to adjacent noncancerous specimens, which implies its vital tumorigenic role . In CRPC cells, elevated p66Shc increases oxidant species production to maintain cell proliferation under androgen-deprived conditions . Besides, p66Shc plays a crucial role in the migration of CRPC cells via ROS-induced activation of Rac1 [45, 46]. However, many other studies reveal that p66Shc is also regarded as an apoptotic mediator independent of the adapter function . Overexpression of p66shc mediates excessive ROS generation and Akt/PKB dephosphorylation, ultimately inducing PCa cell death .
3. Cellular Detoxification from ROS of PCa
Enzymatic or nonenzymatic antioxidants involved in scavenging of different types of ROS play crucial roles in protecting tissues and cells from free radical-mediated oxidative damage . Kelch-like ECH-associated protein 1 (Keap1)–Nrf2/antioxidant responsive element (ARE) acts as an essential modulator initiating antioxidant defenses and contributes to the progression of several tumors . As a specific negative regulator, Keap1 binds to Nrf2 in the cytoplasm, thus inducing Nrf2 ubiquitination and subsequent degradation by the proteasome. While oxidative stress dissociates the Nrf2–Keap1 complex, the transcription Nrf2 transfers into the nucleus and combines with ARE in the promoter regions of the downstream genes to activate the transcriptional expression of antioxidant enzymes [50, 51]. The targets of Nrf2 refer to superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and heme oxygenase-1 (HO-1), which constitute the primary endogenous antioxidant defense system located in the mitochondria and cytoplasm . SOD and CAT are generally functioned against elevated superoxide anion and hydrogen peroxide, respectively . Nonenzymatic scavengers mainly include thioredoxin (Trx), glutathione (GSH), as well as low-molecular-weight antioxidants like cytochrome c and coenzyme Q. The process that GSH is oxidized to GSH disulfide (GSSG) through the interaction with GSH S-transferase directly or via a reaction catalyzed by GSH-Px could alleviate oxidative damage through decreasing disulfide bonds of cytoplasmic proteins to cysteines . Excessive ROS can induce an oxidized Trx form, which is subsequently converted to a functionally reductive form by thioredoxin reductase (TrxR) to maintain redox homeostasis in cells  (Figure 1). Despite lower antioxidant capacity as compared with normal cells, PCa cells adaptively synthesize more antioxidants like HO-1, Nrf2, and GPXs to cope with the continued ROS production. A wealth of studies have suggested that under the dynamic nonequilibrium of ROS, elevated antioxidant genes facilitate the maintenance of protumorigenic signaling and protect against oxidative-dependent death within tumor cells . There is a 45% failure of PCa patients after high-dose radiotherapy against localized diseases, which may be partially due to elevated basic Nrf2 gene expression essential to resist hazardous environmental insults . Overexpression of antioxidant gene KLF4 restores the redox balance of PCa cells and reduces ROS-dependent cell death induced by chemotherapy drugs, such as high concentrations of H2O2 and paraquat [56, 58]. The silence of the KMTD2 gene could weaken the combination of antioxidant genes with FOXO3 DNA to downregulate the expressions of antioxidants, thereby enhancing the chemosensitivity of PCa cells . MiR-17-3p inhibits expressions of mitochondrial antioxidant enzymes to reduce the radioresistant capacity of PCa cells . In conclusion, we could pay attention to the significant role of antioxidant genes in the development of resistance to oxidative stress in PCa and develop new efficient drugs targeting antioxidants.
4. Roles of ROS Molecules in PCa
A moderate level of ROS guaranteed by redox balance is essential for physiological activities via the activation or inactivation of metabolic enzymes, as well as the regulation of calcium in mammalian cells . Once the redox status deviates to oxidation, increased ROS can cause oxidative damage and regulate signaling pathways, further affecting several cancer hallmarks such as survival, proliferation, angiogenesis, invasion, and metastasis in a concentration-dependent manner . In a study performed on PCa cell lines, the proliferative activity of LNCap cells exposed to low concentrations of H2O2 increases. Still, it returns to the pretreatment level after continued exposure to the antioxidant HDL that can counteract the elevated ROS induced by H2O2 . Furthermore, according to the redox imbalance of tumor cells, we can filter several indicators including increased 8-hydroxydeoxyguanosine or F2-isoprostane in urine and decreased levels of the antioxidant-tocopherol or increased peroxide levels in serum as diagnosis and prognosis markers in PCa .
The mechanisms of ROS on the biological manifestation of PCa have been vividly discussed in the latter sections. An excessive or extremely deficient level of ROS increases the chances of cell death or inhibits cell growth through mediating ROS-dependent signaling cascades, which represents a novel anticancer therapeutic strategy based on ROS regulation.
4.1. ROS and Prostate Carcinogenesis
Tumorigenesis is associated with genotype changes and progressive abnormalities of phenotype. In general, a higher level of ROS in PCa causes oxidative damage of crucial cellular constituents (proteins, lipids, DNA, and RNA), further inducing gene mutation and abnormal activation of cellular signaling pathways, eventually contributing to the early events involving tumorigenesis and tumor progression.
ROS lead to DNA damage through mediating single or double-strand breakage as well as pyrimidine and purine lesions . The accumulation of DNA damage via incomplete repair or misrepair can disrupt genome stability and trigger consequently transformation, especially if combined with a deficient apoptotic pathway . Furthermore, numerous reports have described that ROS, as a direct DNA mutagen, activate several oncogenes (receptor tyrosine kinases, Src, and Ras) and inactivate several tumor suppressor genes (PTEN, p53, and TSC2), thus contributing to malignant cellular transformation and the activation of stress-responsive survival pathways [66, 67]. Profound cellular oxidative stress induces lipid peroxidation, promoting the generation of 4-hydroxy-2-nonenal and 1, N6-ethenodeoxyadenosine, which subsequently facilitated mutations of the p53 [68, 69]. Conversely, the active K-ras and deficient p53 further accelerate the ROS accumulation through leading to mitochondrial dysfunction or induction of NOX family proteins, which is necessary for their tumorigenicity [70–73]. Nox5-derived ROS mediate the proliferation and survival of PCa cells through enhancing PKCζ expression and inducing phosphorylation of JNK1/3 . Moreover, several proteins translationally lose regulatory functions due to ROS-dependent modifications of cysteine residues, such as disulfide formation, S-nitrosylation, and reversible glutathionylation . PTEN, as a representative tumor suppressor, is dysregulated in PCa, and PTEN deletion is already characterized by a poor prognosis . Mechanically, ROS can induce the formation of a disulfide bond between the active site cysteine (C71) and another adjacent cysteine (C124) to suppress PTEN activity, thus activating constitutively AKT signaling and further enhancing aberrant growth of the PCa . A previous experiment observed ROS increased CXCR4-mediated metastasis via the inactivation of PTEN in PCa cells .
Epigenetics is regarded as mitotically heritable changes in the expression of genes that maintain the intrinsic DNA sequences. Previous studies suggested ROS may be involved in epigenetic instability/cascade to initiate carcinogenesis, which was a near-universal feature of human cancers [79, 80]. ROS increase the expression of DNA methyltransferases (DNMT) enzymes that either catalyze the transfer of a methyl group to DNA or speed up the reaction of DNA with the positive-charged intermediate S-adenosyl-L-methionine through deprotonating the cytosine molecule at the C-5 position in the process of DNA methylation [81, 82]. Recent evidence shows that overexpression of DNMT plays critical roles in progression, metastases, and therapy resistance of PCa, particularly in advanced stage [83, 84]. ROS can evoke the repression of CDH1 to enhance the epithelial-mesenchymal transition (EMT) process through methyl modification of chromatin . Furthermore, ROS accelerate progression to a malignant phenotype through mediating histone modification that is mainly dependent on histone acetyltransferase (HAT) and histone deacetylase (HDAC). Histone H3 acetylation regulated by ROS promotes the EMT process . As enhancer activity markers, histones acetylation (H3K27ac, H3K9ac) may modulate antioxidative gene transcription by adjusting the spatial structure of chromatin . Besides, it has been reported that decreased overall histone acetylation or elevated nuclear levels of acetylated histone 2A.Z were closely associated with poorer outcomes of PCa [88–90].
ROS function as redox messengers at modest levels to mediate PCa progression via regulations of various signaling molecules. Many transcription factors that include HIF-1, NF-κB, and AP-1 are redox-sensitive, and thiol oxidation of these proteins can alert their DNA-binding activity to have an indirect effect on DNA . After elevated intracellular ROS levels, stabilization of HIF-1α plays a vital role in cell transformation . ROS can activate NF-κB/IL-6/IL-8/pSTAT3 pathway to enhance the proliferation and metastasis of PCa cells [92–94]. Also, AP-1 has been described to regulate the initiation and recurrence of prostate cancer via activating constituent downstream genes like c-Jun and c-Fos .
Additionally, the raised levels of mitochondrial ROS induce abnormal activation of mitogen-activated protein kinase (MAPK)/extracellular-signal-related kinase (ERK) [96–98] for survival and the increased resistance to apoptosis . As mentioned above, the dismantlement of the Nrf2-Keap1 complex is due to the oxidized cysteine residues of Keap1 induced by ROS. Besides the effect of ROS detoxification, Nrf2 activation increases cell viability and improves the invasive and migratory abilities of PCa cells via EMT . In conclusion, inhibitors of ROS generation in PCa cells could effectively suppress genetic instability and initiation of redox signaling cascades, resulting in fewer metabolic adaptations and less proliferation and survival.
4.2. ROS and Androgen Receptor(AR)
AR is a nuclear receptor transcription factor with the three-dimensional crystal structure containing the ligand-binding domain (LBD) and DNA binding domain (DBD). It is essential to aggressiveness and progression of PCa . Androgens activate AR signaling by binding to AR to drive the growth as well as metastasis and simultaneously suppress apoptosis of PCa cells [102–104]. Previous studies have shown that ROS production or oxidative stress-associated markers are required for androgen stimulation in AR-positive cells. ROS have been proposed to stimulate the AR nuclear translocation and AR-mediated transcriptional activity via inducing PTEN loss . There is close proximity as well as the overlap between AR response elements and binding sites for NF-κB, so ROS-mediated activated NF-κB may bind directly to the AR promoter to alter AR DNA binding activity and its downstream gene transcription .
The commonly targeted genes of AR signaling contain prostate-specific antigen (PSA), B-cell lymphoma-extra large (Bcl-xL), and NK3 homeobox 1 (NKX3.1), which are highly expressed in metastatic PCa and CRPC . The increased levels of PSA in serum are considered as a sensitive marker for the development and progression of PCa . PSA releases insulin growth factor-1 (IGF-1), thus catalyzing IGFBP-3 to promote the proliferation of PCa . ATD remains a routinely adopted therapy for locally advanced and metastatic prostate cancer through inhibiting the androgen biosynthesis or preventing androgen from binding to AR. However, after a period of treatment, the majority of patients eventually progress into CRPC which is primarily driven by the aberrant AR activities including AR gene amplification, mutations on AR gene ligand-binding domain, and elevated AR coactivators as well as AR splice variants [110–112].
Recent studies indicate that androgen effects might not be equal to the AR effects. Besides, androgen-independent (AI) cells have a higher level of oxidant species than androgen-sensitive (AS) cells, which suggest that ROS can cause deregulations of the AR axis pathway . It is reported that AI PCa cells exhibited higher p66Shc protein levels that activate NOX complexes and stimulate mitochondrial superoxide production for intracellular ROS generation to a high degree . Additionally, there is a lower glutathione (GSH) content and GSH/glutathione disulfide ratio in PC-3 cells that serve as a representative of AI PCa cells . In comparison to the C4-2B/LNCaP cells, PC-3 cells show a significant increase in Trx1 protein levels; however, the decrease of total Trx activities and higher oxidation of Trx1 resulting from reduced TrxR1 or increased TXINP, also correlated with higher levels of ROS in PC-3 cells . Inversely, the upregulated ROS levels accelerate the proliferation and metastasis of PC-3 cells via mediating the specific absence of the P53 gene and PTEN gene, as well as the constitutive activation of PI3K/AKT signaling [116–118]. ROS positively modulate AR expression or possibly AR mRNA stabilization . ROS not only upregulate TXNDC9 expression for MDM2 degradation but also enhance PRDX1-mediated AR protein stabilization and subsequent AR signaling transactivation . Antioxidant Trx1 inhibition also elevates ROS-dependent AR levels of CRPC when combined with ADT . Overexpression of Nrf2 can suppress AR expression and function in PCa cells via decreasing ROS levels . Under the castrated levels of androgens, hypoxia enhances the transcriptional activity of AR through ROS-mediated HIF-1α . Alternately, due to mutations of the ligand-binding domain (LBD) partially induced by ROS, abnormal activation of AR signaling also occurs in response to growth factors, cytokines, and kinases, which disengages tumors from hormone-dependent environments. Targeting the AR for direct degradation may lead to better efficacy to further suppress the PCa progression. Enzalutamide, an FDA-approved targeted AR inhibitor, is commonly prescribed to prolong overall and progression-free survival in patients . However, some limitations by the resistance of such intrinsic drugs eventually cause the failure of therapy. More pieces of evidence demonstrate that the emergence of variant types of AR is associated with the progression of CRPC, and reversing the phenomenon could improve the prognosis of PCa . ROS has been shown to induce splice variants of AR and augment AR-Vs-expressions via mediating NF-κB activation in PCa cells . Additionally, ROS could have a direct effect on the expression of several splicing factors like heteronuclear ribonucleoproteins (hnRNPs) that play critical roles in AR expression and production of variants in PCa . Despite lacking the ligand-binding domain, the most significant AR-V7 remains constitutively active under the castrated levels of androgens. It stimulates the transcriptional activation of AR target genes as it still retains the transactivating N-terminal domain (NTD) . Conversely, AR expression is vital for redox homeostasis . Activated AR pathway facilitates ROS production most strongly in an environment deficient of androgen. AR signal mediates malignant biological behaviors of CPRC at least in part by stabilizing the posttranslation of p66shc and increasing p66Shc protein levels .
Contradictorily, some evidence reveals that extremely high levels of ROS could negatively regulate the translational levels of AR. Isoselenocyanate-4 (ISC-4) inhibited LNCaP cell growth and survival via ROS-mediated suppression of AR and PSA abundances without initially decreasing their steady-state mRNA level . ABT263 drug could increase ubiquitin/proteasome-dependent degradation of AR and AR-v7 proteins through the ROS/USP26 axis, enhancing CRPC cell sensitivity to Enzalutamide . Besides, acute exposure (2 h) to CDDO-Me increased ROS levels to suppresses AR and its splice-variant AR-V7 at both the transcriptional and translational levels .
There seems to be a regulatory loop between AR and intracellular ROS, which suggests that AR activity is regulated by ROS and AR signaling functions via mediating ROS generation. Further exploration of specific crosstalk between ROS and AR has been shown broad prospects of treatments for PCa.
4.3. ROS and Tumor Microenvironment (TME)
The TME is extraordinarily complex and dynamically variable . Compared to adjacent healthy tissue, tumors are known to have a highly oxidative microenvironment, which may play a crucial step in the interactions between tumor cells and the surrounding stromal cells. TME is mainly divided into two aspects: nonimmune microenvironment dominated by fibroblasts and immune microenvironment based on immune cells. It is generally accepted that PCa cells acquire a symbiotic relationship with TME. The reciprocal crosstalk between them occurs via various intercellular communications such as direct cell-to-cell contact, migration of extracellular vesicles (EVs), and chemokines/cytokines secretion partially induced by ROS, jointly leading to tumorigenesis and progression [133, 134]. Lysophosphatidic acid LPA of TME binding to LPA1–3 receptors of PCa cells promotes calreticulin (CRT)/vegf-c expression to induce lymphangiogenesis and lymphatic metastasis through ROS-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) . ADT induces the migration of mesenchymal stem cells (MSCs) into tumor tissue via the ROS/NF-κB/IL-1β pathway of PCa cells. MSCs, in turn, increase the stemness of PCa cells via secreting chemokine ligand 5 under the AD condition .
As a significant component of tumor stroma, cancer-associated fibroblasts (CAFs) promote the proliferation and metastasis of PCa cells through the TGF-β pathway . CAFs have been revealed to enhance the numbers of PCa stem cells and be involved in the PCa angiogenesis and chemoresistance . Moreover, CAFs increase glutathione levels of PCa cells to counteract drug-induced oxidative death . Emerging evidence suggests TGFβ1-mediated CAFs activation is associated mainly with Nox4-derived ROS signaling . Redox-dependent CAFs activation has the immunosuppressive function via phosphorylation of JNK [140–143]. CAFs broadly suppressed immune response by explicitly excluding CD8+ T cells from tumors through upregulating NOX4 levels . Similarly, NOX4-mediated ROS play a key role in CAFs-induced functional cell reprogramming from monocytes into immunoinhibitory MDSCs that inhibit T-cell proliferation and impair T-cell function .
As a prominent component in infiltrating immune cells, tumor-associated macrophage (TAM) accounts for up to 70% of prostate tumor immune subsets . Macrophages are well known due to their heterogeneity and plasticity, which generally polarize towards two extremes, the tumor-suppressing M1 phenotype or tumor-promoting M2 phenotype. The recruitment and functional evolution of macrophages in TME can be modulated by various cytokines, tissue factors, and conditions . CCL2-secreting CAF facilitates the recruitment of TAM from systemic sites to the microenvironment of PCa . ADT induces ROS-dependent expression of colony-stimulating factor 1 (CSF1) that leads to a significant enhancement of TAM infiltration and skews them towards the M2 phenotype in PCa . On the other hand, the soluble mediators released by PCa cells could aid in polarization to the M2 phenotype, such as IL-6 [150, 151]. Hypoxia enhances the Warburg effect of PCa cells via HIF-1 expression, thus inducing secretion of exosomes rich in lactate, which could promote TAM towards the M2 phenotype . Several studies specifically implicate that high percentages of activated M2 phenotype in the TME are a hallmark of cancer, and usually predict poor clinical prognosis in PCa patients. As such, PCa patients with elevated M2-TAMs infiltration have shown an increase in the probabilities of dying . A wealth of studies have revealed immune cells release profound cytokine to stimulate NOX-mediated ROS production within tumor cells, which alters DNA integrity and enhances the angiogenic process . M2-phenotype-secreted CCL5 results in PCSCs self-renewal and PCa cell metastasis via activating β-catenin/STAT3 signaling .
Indeed, the M1 phenotype enhances phagocytosis by ROS-mediating NF-κB activation and tolerates a broader range of ROS levels . However, despite having lower ROS levels than the M1 macrophages, M2 macrophages still require moderate ROS for polarization and become more vulnerable to alterations in cellular redox status. Luput et al. reported the significant role of NADHP oxidase in the modulation of the protumor actions of M2-macrophages . The ROS generation in M2 macrophages is required for the synthesis of MM2 and MMP9, which is followed by the metastasis of PCa cells. Additionally, M2 macrophages exhibit elevated expressions of some crucial antioxidants . Nrf2 activation of M2 macrophages increases vascular endothelial growth factor (VEGF) expression and contributes to the EMT process of tumor cells . Given the key redox differences, ROS scavengers can decrease ROS levels to attenuate polarization of the M2 but not the M1 macrophages, such as MnTE and the pan-Nox inhibitor, diphenyleneiodonium (DPI) .
As signal molecules, ROS may decrease PCa cell immunogenicity by bypassing the surveillance of immune cells. In PCa cells, ROS-induced PTEN loss increases IDO1 protein expression and FoxP3+ Treg density of TME, thereby triggering an immunosuppressive state and promoting tumor growth and invasion [160, 161]. High CD8+ T cells infiltration correlates with a good prognosis due to their cytotoxic functions in many solid tumors [162, 163]. However, vast stromal CD8+ T cells are associates with poor prognosis in radical prostatectomy specimens and shorter time until BCR in PCa patients . These findings indicate that CD8+ T cells in the microenvironment of PCa may be senescent, dysfunctional, or suppressed. Mechanically, nonfunctional CD8+ T cells upregulate their negative coinhibitory markers or downregulate the positive costimulatory molecules, thereby resulting in the suppression of antitumor immune responses . Previous preclinical studies have reported that overexpression of lymphocyte activation gene-3 (LAG-3) as the coinhibitory molecules on CD8+ T cells can regulate T-cell tolerance to tumor antigens . In particular, the PD-1/PD-L1 axis acts as a crucial regulator of immune checkpoints to suppress the adaptive immune system. The PD-1 is mainly expressed on T cells, and its ligand PD-L1 is commonly expressed on tumor cells. Once PD-1 binds to PD-L1, PCa cells block the active cytotoxic function of T lymphocytes through immune evasion . Emerging evidence demonstrates that ROS have a significant influence on the expression of PD-1 and PD-L1. An enhanced generation of ROS usually promotes PD-L1 expression on the surface of tumor cells as well as PD-1 expression on T cells via multiple signaling factors such as HIF-1, JAK/STAT3, and NF-κB . Inversely, ROS scavenging directly represses their expressions in general. Furthermore, a potent ROS scavenger also selectively inhibits M2 macrophage polarization, indirectly limiting or decreasing the expression of PD-L1 . It is noteworthy to investigate the specific mechanism of the effect of ROS on TAM differentiation and regulation of the PD-(L)1 immune checkpoint.
4.4. ROS and Cytoprotective Autophagy
Autophagy is a “self-feeding” phenomenon that allows lysosome to degrade damaged, senescent, or nonfunctional proteins and organelles. It is an evolutionarily conserved biological process in eukaryotic cells and plays a vital role in maintaining cell homeostasis and renewal [168, 169]. In healthy cells, autophagy proceeds at a basic level to prevent tumor initiation by inhibiting inflammation and chronic tissue damage and maintaining genome integrity . Nassour demonstrated that both insufficient and absent autophagy was necessary for tumorigenesis [171, 172]. Monoallelic loss of the essential autophagy gene BECN1, MAPLC3, and ATG5 has been frequently found in PCa. In part, deletions of BECN1and ATG5 are a driver of prostate tumorigenesis via disordered degradation of damaged mitochondrial and ROS-mediated DNA damage . In contrast, autophagy has recently emerged as a critical regulator of multiple processes of cancers and is usually correlated with the development and progression of tumors. In cancerous cells where malignant transformation has been completed, elevated autophagy can provide anabolic energy and raw materials through recycling components of nonfunctional organelles to mediate the growth of tumor cells [173, 174]. Tumor cells can evade apoptosis through autophagy regulation, thus increasing drug resistance and enhancing tumor cell viability . Although many cancers, such as prostate cancer, exhibit elevated autophagy levels, the regulatory mechanisms of this process are still not clear.
A recent report reveals 35% of PCa patients with a high Gleason score (GS) show an increase in the vital autophagy proteins (p62). It has been identified that genetic alterations and androgen are responsible for autophagy activation in PCa. The lysine demethylase KDM4B significantly increases the LC3 puncta and the protein levels of LC-3II by activating Wnt/β-catenin signaling, which indicates that upregulated KDM4B facilitates autophagy activation. Importantly, specific autophagy inhibitor (3-MA) partially attenuates KDM4B-induced CRPC cell proliferation . Furthermore, overexpression of NPRL2 promotes docetaxel chemoresistance of CRPC cells by regulating autophagy via mTOR signaling . Also, androgen induces autophagy and autophagic flux of PCa cells through the AR pathway to promote cell proliferation [177, 178]. Indeed, the mRNA and protein levels of 4 core autophagy genes: ULK1, ULK2, ATG4B, and ATG4D are upregulated by androgen and correlate with poor prognosis of PCa .
One of the downstream processes affected by redox imbalance is autophagy. Currently, some significant modes of ROS-regulated autophagy have been revealed. The oxidation and inactivation of Atg4A by ROS leads to the conjugation of LC3 to phosphatidylethanolamine, inducing autophagy activation . Additionally, ROS directly upregulate expression of BNIP3 via activating HIF-1, thus inhibiting mTOR activity that is negatively associated with autophagy activation . Inhibition of mTOR is also generated by activated TSC2 due to ROS-mediated the oxidation of ataxia telangiectasia mutated (ATM) . In contrast, autophagy is a self-defense mechanism by which PCa cells withstand excessive oxidative stress. Especially when there exists a high level of p62 in PCa cells, autophagy can cause the degradation of Keap1 depending on the direct physical interaction between Keap1 and p62, thus limiting ROS amplification through Nrf2/ARE axis [182, 183].
Recent shreds of evidence demonstrate that autophagy activation is generally accompanied with ROS that function as crucial molecules in the crosstalk between autophagy and apoptosis . Mechanically, excessive ROS generate an autophagy-dependent cytoprotective response through inducing activations of multiple signalings, such as AMPK/ERK and NF-κB, which attenuates original ROS-mediated apoptosis . Besides, ROS induce the phosphorylation of beclin1 and Bcl-2 through abolishing the interaction between them, thus accelerating the activation of autophagy and apoptosis .
According to reports in the literature, various anticancer drugs, such as lasalocid and adriamycin, have been confirmed to activate the ROS-dependent autophagy, which has negative impacts on their proapoptotic effects. Resulting in cytotoxic apoptosis of PCa cells, lasalocid simultaneously induces ROS-dependent cytoprotective autophagy. Thus, autophagy inhibitor (3-MA) enhances lasalocid-induced apoptosis, which might result from elevated ROS production . Similarly, the combination of adriamycin with the late phase autophagy inhibitor (CQ) resulted in more pronounced tumor suppression of PCa cells . These results indicate that ROS-mediated autophagy acts as a protector for PCa cell survival. In this context, it could be assumed that the addition of agents that inhibit ROS-reactive cytoprotective autophagy enhances the proapoptotic effect of various cancer therapies .
Indeed, autophagy, as a “double-edged” sword, plays a complex and paradoxical role depending on different stages of cancer development and cell type . The cytotoxic autophagy triggers cell death (named autophagic cell death), which will be discussed in detail below.
4.5. ROS and Cell Death
Due to a lower capacity of the antioxidant system, tumor cells are more sensitive to fluctuations in ROS levels than healthy cells. This accumulation of cellular ROS upon overwhelming amounts may induce secondary oxidative damage and lead to various types of PCa cell death including apoptosis, autophagic cell death, necrosis, and ferroptosis. Emerging evidence indicates that several anticancer agents require upregulation of ROS levels to mediate tumor cell death. Therefore, increasing intracellular levels of ROS over a threshold could be a novel therapeutic strategy.
Apoptosis, also known as type I genetically programmed cell death, is a normal biological process described by stereotypical morphological alterations involving nuclear fragmentation and condensation, membrane blebbing, and apoptotic body formation [189, 190]. Two significant apoptosis pathways have been reported: the mitochondria-mediated pathway and death receptor-mediated pathway, which depend on the caspase activation . A wealth of studies highlight ROS serve as a significant role in chemotherapy and radiotherapy against various cancers. It has been proved that high levels of ROS above a toxic threshold cause mitochondrial dysfunction and activate death receptors [192, 193]. Mitochondria are both the primary source of ROS generation and the pivot of intrinsic apoptosis regulation. ROS can trigger the opening of permeability transition pore on the mitochondrial membrane by regulating the Bcl-2 family, thus leading to increased mitochondrial membrane potential (MMP) loss, which is thought to be an early event and a possible cause of programmed cell death [194, 195]. In addition to blocking cell cycle at G1 phase, which is partly associated with ROS-mediated cell injury, oleanolic acid methyl ester (OAME) also induces ROS-dependent MMP loss, the release of cytochrome c, and activation of caspase 7/3. These caspases mediate the execution phase of apoptosis with a cascade of proteolytic activity. It indicates that OAME triggers ROS-mediated apoptosis of PCa cells through targeting the mitochondrial pathway [196, 197]. Due to the loss of cytochrome c from the mitochondria, profound cytochrome c forms a complex with apoptotic protein-activating factor 1 (Apaf-1) to activate caspase cascades and further increases production of ROS following disrupting the mitochondrial ETC . The extrinsic pathway is activated upon binding of proapoptotic ligands to corresponding death receptors including Fas, TNF receptor 1 (TNFR1), TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), and TRAIL receptor 2 (TRAIL-R2) . ROS may induce the DNA damage-dependent ATM and ATR activation of PCa cells, upregulating the expression of DR5 (TRAIL-R2) and Fas (CD95) proteins on the membrane, thus resulting in caspase 8 activation/PARP cleave and subsequently triggering apoptotic pathway. Furthermore, ROS mediate TRAIL/FasL signaling between NK cells and tumor cells to enhance the lethality of NK cells .
Additionally, a galaxy of research findings have demonstrated that ROS act as upstream signaling molecules to hinder accurate protein folding processes and disturb endoplasmic reticulum (ER) homeostasis, which can be called as ER stress. Severe ER stress has the ability to initiate another atypical intrinsic apoptosis response . Induction of ER stress activation and PCa cell apoptosis by both Chelerythrine (CHE) and Isoalantolactone (IALT) is dependent on ROS generation [193, 201]. Mechanically, IALT increases the levels of ROS-dependent p-eIF2α and ATF4 in the PC-3 and DU145 cells, thus stimulating expression of the transcription factor CHOP that inhibits the expression of Bcl-2 and is strictly responsible for the initiation of the cell apoptosis cascade [201–203]. Mitochondrial outer membrane permeabilization (MOMP) also results in elevated cytoplasmic proapoptotic molecules containing apoptosis-inducing factor (AIF) and endonuclease G (Endo G) in response to organelle damage induced by ROS, and these molecules function in a caspase-independent manner . As such, Auriculasin-induced ROS initiate apoptosis of PCa cells through the elevated release of AIF and Endo G via the depolarization of the mitochondrial membrane .
As mentioned above, autophagy can also function as a tumor suppressor mechanism in response to various stressors like oxidative stress (179). Autophagy-associated cell death, especially autophagic cell death, is called type II programmed cell death and partly results from mitochondria dysfunction [205, 206]. Once ROS levels surpass the cellular antioxidant capacity, autophagy may fail to remove the excess ROS that persistently damage mitochondria, resulting in autophagy-associated cell death. Additionally, continuous or excessive induction of autophagy serves as a “pro-death” signal, leading to inordinate cell degradation and self-digestion of vital cellular components via accumulation of autophagic vacuole, eventually resulting in autophagic cell death in a caspase-independent pathway [207, 208]. An arsenic compound KML001 induced ROS-dependently upregulation of autophagic specific protein LC3, which is followed by an increase in cell death (autophagic cell death) . Furthermore, the induction of autophagic cell death by small molecules can enhance the antitumor activity of radiation therapy or chemotherapy.
As nonprogrammed cell death, necroptosis is initially described as a passive mechanism of cell demise. It is characterized by the morphological traits containing rounding of the cell, organelle swelling, plasma membrane rupture, and leakage of nuclear constituents with the inflammatory surrounding [210, 211]. Cancer cells preferentially depend on glycolysis (Warburg effect) for ATP production in hypoxia conditions, which endows selective advantage in the presence of diminished nutrition but results in tumor cells more sensitive to glycolysis inhibition . The glucose analog 2-deoxy-d-glucose (2DG), an inhibitor of glycolysis and glucose transport, can reduce intracellular ATP levels and cause elevated ROS generation, finally culminating in necrotic cell death . A single agent 2DG can induce cytotoxic effects on PCa cells . Furthermore, various evidences have proved that the key enzymes in glycolysis, such as HK2, PFK, and PK, play vital roles in the survival of PCa cells . Selenite induces necrotic cell death of PCa cells through triggering ATP depletion via inhibiting PFK activity, whereas N-Acetyl-cysteine (NAC) can rescue selenite-induced ATP depletion and PFK activity, which indicates that ROS are involved in necroptosis through inhibiting PFK activity directly or indirectly .
Further researches have revealed that necrosis is a regulated process critically dependent on a complex consisting of RIP1, RIP3, and MLKL [210, 216]. Necroptosis is usually accompanied by an intense burst of ROS production. However, it is not the direct executioner of necroptosis . Recruitment and activation of RIP3 dependent on RIP1 phosphorylation can lead to MLKL phosphorylation through ROS generation by the activation of the pyruvate dehydrogenase complex . ROS-dependent MLKL activation triggers its oligomerization and membrane translocation to stimulate the formation of pores and the influx of ions (mainly calcium) on the membrane, eventually resulting in the rupture of cell membranes and cell death [218, 219].
Ferroptosis is characterized by the accumulation of lipid hydroperoxides (LOOH) and high expression of HO-1 in an iron-dependent manner . While accompanying with augmented lipid peroxidation and glutathione depletion, excessive antioxidant HO-1 may behave in prooxidant compounds following a direct reaction with ROS in the conditions of transition of metal ions such as copper and iron, eventually leading to cell death through a process called as ferroptosis . ALZ003 potently triggered the ferroptosis of PCa cells by impairing AR-regulated GPX4 that is a GSH-dependent enzyme required for the elimination of lipid .
4.6. Challenges and Opportunities Related to the Chemoprevention of PCa by the Antioxidants
Epidemiological evidence strongly suggested that a lower risk of cancer was associated with higher consumption of vegetables and fruits . Therefore, the researches of naturally available pharmaceutical agents against PCa are of particular interest. Several clinical trials pointed out the properties of the popular antioxidants, such as some minerals (selenium), vitamins, and polyphenols, and showed their encouraging results against PCa prevention (Table 1). However, some contradictory data questioned the clinical effects of antioxidants on human health. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large intervention study, revealed that the supplement of selenium + vitamin E had no effect on reducing PCa risk. Surprisingly, single vitamin E supplementation increased the risk of PCa [223, 224]. In a separate study, higher baseline selenium was associated with a higher risk of increased PSA velocity in nonmetastatic PCa . Grant has observed a positive relationship between vitamin D intake and PCa . The different results may be due to improper dosage, formulation, intervention periods, and patient populations. Anyhow, there is a large quantity of challenges and opportunities in the antioxidative treatment models for PCa prevention. The possible application of any discovery seems staggering in the field of public health. Further clinical studies are warranted to carry out a large-scale cohort study in multiple regions and control several potential confounders in the analysis. Eventually, we select an optimal combinatorial approach of antioxidants against different individuals to reduce the risk of morbidity and mortality of PCa.
Abbreviations: PSA: prostate-specific antigen; GPX 1: glutathione peroxidase 1; NOX: NADPH oxidase; SOD: superoxide dismutase; NF-κB: nuclear factor kappa-B; HIF-1α: hypoxia inducible factor-1α; HG-PIN: high-grade prostatic intraepithelial neoplasia; CAT: catalase.
Based on the diversified functions and interactions of ROS as well as a certain degree of understanding on aetiology of PCa, ROS have been identified to play critical roles in the pathogenesis of PCa. One characteristic of PCa cells that distinguishes them from normal cells is having higher ROS levels associated with upregulated key components of ROS producers and antioxidant enzymes/peptides. These components include ETC, NOXs, p66Shc, Nrf2, TRx, and GSH. A moderate level of ROS is required for the progression of PCa via ROS-dependent reduction-oxidation reactions and signaling pathways, such as genetic instability, epigenetics aberrations, AR signaling, and autophagy. Additionally, the oxidative microenvironment of PCa resulting from a group of various nonmalignant cells with large amounts of ROS, like CAFs, TAM, and T cells, provides favorable circumstances that contribute to drug resistance, metastasis, and immune evasion of PCa cells. However, elevated levels of ROS generated to toxic levels or exhaustion of the critical antioxidant system capacity would result in PCa cell death (Figure 2). ROS regulations represent a potential target for the treatment of PCa. Currently, given that ROS are also an “Achilles’ heel” in tumors, two strategies have been developed . The treatment with natural antioxidants is regarded as an essential focus on retarding PCa progression via quenching ROS and reducing oxidative stress. As such, the use of antioxidants significantly enhances the antitumor efficacy when synergistically combined with other therapeutics that induce cell death independent of oxidative stress. On the other hand, a further elevation in the ROS level mediated by ROS producing agents or those abrogating the inherent antioxidant system crosses the tolerable threshold, thus resulting in various types of cell death. In this regard, most of the currently available prostate cancer therapeutics are highly dependent on ROS-developed cytotoxicity. In summary, the results of this study indicate that ROS, as a common proliferative and apoptotic convergent point, regulate the biological behaviors subtly in terms of different cellular environments. However, it is necessary further to shed light on the exact mechanism of ROS influencing PCa.
Conflicts of Interest
All authors declare that they have no conflicts of interest related to this paper.
Chenglin Han analysed and interpreted the relationship of ROS and prostate cancer and wrote the original draft; Chenglin Han, Zilong Wang, and Yingkun Xu performed the article revision. Shuxiao Chen, Yuqing Han, and Lin li performed the supervision; Muwen Wang and Xunbo Jin obtained funding and approved the final manuscript. This work was supported by the National Natural Science Foundation of China (Grant No. 81572534) and Natural Science Foundation of Shandong (Grant No. ZR2016HM32).
- N. A. Abd Wahab, N. H. Lajis, F. Abas, I. Othman, and R. Naidu, “Mechanism of Anti-Cancer Activity of Curcumin on Androgen-Dependent and Androgen-Independent Prostate Cancer,” Nutrients, vol. 12, no. 3, p. 679, 2020.
- R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2020,” CA: a Cancer Journal for Clinicians, vol. 70, no. 1, pp. 7–30, 2020.
- F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, “Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries,” CA: a Cancer Journal for Clinicians, vol. 68, no. 6, pp. 394–424, 2018.
- W. Chen, R. Zheng, P. D. Baade et al., “Cancer statistics in China, 2015,” CA: a Cancer Journal for Clinicians, vol. 66, no. 2, pp. 115–132, 2016.
- A. Jemal, M. M. Center, C. DeSantis, and E. M. Ward, “Global patterns of cancer incidence and mortality rates and trends,” Cancer Epidemiology, Biomarkers & Prevention, vol. 19, no. 8, pp. 1893–1907, 2010.
- Y. Niu, C. Guo, S. Wen et al., “ADT with antiandrogens in prostate cancer induces adverse effect of increasing resistance, neuroendocrine differentiation and tumor metastasis,” Cancer Letters, vol. 439, pp. 47–55, 2018.
- K. Sinha, J. Das, P. B. Pal, and P. C. Sil, “Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis,” Archives of Toxicology, vol. 87, no. 7, pp. 1157–1180, 2013.
- B. C. Dickinson and C. J. Chang, “Chemistry and biology of reactive oxygen species in signaling or stress responses,” Nature Chemical Biology, vol. 7, no. 8, pp. 504–511, 2011.
- S. Mendes, F. Timoteo-Ferreira, H. Almeida, and E. Silva, “New insights into the process of placentation and the role of oxidative uterine microenvironment,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 9174521, 18 pages, 2019.
- R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2017,” CA: a Cancer Journal for Clinicians, vol. 67, no. 1, pp. 7–30, 2017.
- D. G. Bostwick, H. B. Burke, D. Djakiew et al., “Human prostate cancer risk factors,” Cancer, vol. 101, no. S10, pp. 2371–2490, 2004.
- M. Schieber and N. S. Chandel, “ROS function in redox signaling and oxidative stress,” Current Biology, vol. 24, no. 10, pp. R453–R462, 2014.
- A. Acharya, I. Das, D. Chandhok, and T. Saha, “Redox regulation in cancer: a double-edged sword with therapeutic potential,” Oxidative Medicine and Cellular Longevity, vol. 3, no. 1, pp. 23–34, 2010.
- D. Trachootham, J. Alexandre, and P. Huang, “Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?” Nature Reviews Drug Discovery, vol. 8, no. 7, pp. 579–591, 2009.
- S. Di Meo, T. T. Reed, P. Venditti, and V. M. Victor, “Role of ROS and RNS sources in physiological and pathological conditions,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 1245049, 44 pages, 2016.
- S. Kroller-Schon, S. Steven, S. Kossmann et al., “Molecular mechanisms of the crosstalk between mitochondria and NADPH oxidase through reactive oxygen species-studies in white blood cells and in animal models,” Antioxidants & Redox Signaling, vol. 20, no. 2, pp. 247–266, 2014.
- R. Kanwal and S. Gupta, “Epigenetic modifications in cancer,” Clinical Genetics, vol. 81, no. 4, pp. 303–311, 2012.
- I. B. McInnes and G. Schett, “The pathogenesis of rheumatoid arthritis,” The New England Journal of Medicine, vol. 365, no. 23, pp. 2205–2219, 2011.
- A. P. West and G. S. Shadel, “Mitochondrial DNA in innate immune responses and inflammatory pathology,” Nature Reviews Immunology, vol. 17, no. 6, pp. 363–375, 2017.
- S. Liu, M. Feng, and W. Guan, “Mitochondrial DNA sensing by STING signaling participates in inflammation, cancer and beyond,” International Journal of Cancer, vol. 139, no. 4, pp. 736–741, 2016.
- A. M. F. Kalsbeek, E. K. F. Chan, J. Grogan et al., “Altered mitochondrial genome content signals worse pathology and prognosis in prostate cancer,” Prostate, vol. 78, no. 1, pp. 25–31, 2018.
- R. Yue, X. Xia, J. Jiang et al., “Mitochondrial DNA oxidative damage contributes to cardiomyocyte ischemia/reperfusion-injury in rats: cardioprotective role of lycopene,” Journal of Cellular Physiology, vol. 230, no. 9, pp. 2128–2141, 2015.
- A. Hahn and S. Zuryn, “Mitochondrial Genome (mtDNA) Mutations that Generate Reactive Oxygen Species,” Antioxidants, vol. 8, no. 9, p. 392, 2019.
- J. A. Petros, A. K. Baumann, E. Ruiz-Pesini et al., “mtDNA mutations increase tumorigenicity in prostate cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 3, pp. 719–724, 2005.
- B. Schöpf, H. Weissensteiner, G. Schäfer et al., “OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation,” Nature Communications, vol. 11, no. 1, p. 1487, 2020.
- G. Tarantino, M. N. Di Minno, and D. Capone, “Drug-induced liver injury: is it somehow foreseeable?” World Journal of Gastroenterology, vol. 15, no. 23, pp. 2817–2833, 2009.
- Y. Wu, C. Hao, X. Liu et al., “MitoQ protects against liver injury induced by severe burn plus delayed resuscitation by suppressing the mtDNA-NLRP3 axis,” International Immunopharmacology, vol. 80, p. 106189, 2020.
- A. P. West, W. Khoury-Hanold, M. Staron et al., “Mitochondrial DNA stress primes the antiviral innate immune response,” Nature, vol. 520, no. 7548, pp. 553–557, 2015.
- C. S. Yang, J. S. Lee, M. Rodgers et al., “Autophagy protein Rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation,” Cell Host & Microbe, vol. 11, no. 3, pp. 264–276, 2012.
- C. S. Yang, D. M. Shin, K. H. Kim et al., “NADPH oxidase 2 interaction with TLR2 is required for efficient innate immune responses to mycobacteria via cathelicidin expression,” Journal of Immunology, vol. 182, no. 6, pp. 3696–3705, 2009.
- Y. Miyata, T. Matsuo, Y. Sagara, K. Ohba, K. Ohyama, and H. Sakai, “A Mini-Review of Reactive Oxygen Species in Urological Cancer: Correlation with NADPH Oxidases, Angiogenesis, and Apoptosis,” International Journal of Molecular Sciences, vol. 18, no. 10, p. 2214, 2017.
- A. Tarafdar and G. Pula, “The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders,” International Journal of Molecular Sciences, vol. 19, no. 12, p. 3824, 2018.
- K. Bedard and K. H. Krause, “The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology,” Physiological Reviews, vol. 87, no. 1, pp. 245–313, 2007.
- S. D. Lim, C. Sun, J. D. Lambeth et al., “Increased Nox1 and hydrogen peroxide in prostate cancer,” Prostate, vol. 62, no. 2, pp. 200–207, 2005.
- B. Kumar, S. Koul, L. Khandrika, R. B. Meacham, and H. K. Koul, “Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype,” Cancer Research, vol. 68, no. 6, pp. 1777–1785, 2008.
- S. Prasad, S. C. Gupta, and A. K. Tyagi, “Reactive oxygen species (ROS) and cancer: role of antioxidative nutraceuticals,” Cancer Letters, vol. 387, pp. 95–105, 2017.
- J. N. Moloney and T. G. Cotter, “ROS signalling in the biology of cancer,” Seminars in Cell & Developmental Biology, vol. 80, pp. 50–64, 2018.
- J. P. Lu, L. Monardo, I. Bryskin et al., “Androgens induce oxidative stress and radiation resistance in prostate cancer cells though NADPH oxidase,” Prostate Cancer and Prostatic Diseases, vol. 13, no. 1, pp. 39–46, 2010.
- J. N. Heinrich, S. P. Kwak, D. S. Howland et al., “Disruption of ShcA signaling halts cell proliferation--characterization of ShcC residues that influence signaling pathways using yeast,” Cellular Signalling, vol. 18, no. 6, pp. 795–806, 2006.
- A. Onnis, C. Cassioli, F. Finetti, and C. T. Baldari, “Regulation of selective B cell autophagy by the pro-oxidant adaptor p66SHC,” Frontiers in Cell and Development Biology, vol. 8, p. 193, 2020.
- M. Giorgio, E. Migliaccio, F. Orsini et al., “Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis,” Cell, vol. 122, no. 2, pp. 221–233, 2005.
- E. R. Galimov, “The role of p66shc in oxidative stress and apoptosis,” Acta Naturae, vol. 2, no. 4, pp. 44–51, 2010.
- R. A. Eid, M. S. A. Zaki, M. Alaa Eldeen, M. M. Alshehri, A. A. Shati, and A. F. El-Kott, “Exendin-4 protects the hearts of rats from ischaemia/reperfusion injury by boosting antioxidant levels and inhibition of JNK/p66Shc/NADPH axis,” Clinical and Experimental Pharmacology & Physiology, vol. 47, no. 7, pp. 1240–1253, 2020.
- S. Veeramani, Y. W. Chou, F. C. Lin et al., “Reactive oxygen species induced by p66Shc longevity protein mediate nongenomic androgen action via tyrosine phosphorylation signaling to enhance tumorigenicity of prostate cancer cells,” Free Radical Biology & Medicine, vol. 53, no. 1, pp. 95–108, 2012.
- D. R. Miller, M. A. Ingersoll, A. Chatterjee et al., “p66Shc protein through a redox mechanism enhances the progression of prostate cancer cells towards castration-resistance,” Free Radical Biology & Medicine, vol. 139, pp. 24–34, 2019.
- M. A. Ingersoll, Y. W. Chou, J. S. Lin et al., “p66Shc regulates migration of castration-resistant prostate cancer cells,” Cellular Signalling, vol. 46, pp. 1–14, 2018.
- L. Liang and Z. Zhang, “Gambogic acid inhibits malignant melanoma cell proliferation through mitochondrial p66shc/ROS-p53/Bax-mediated apoptosis,” Cellular Physiology and Biochemistry, vol. 38, no. 4, pp. 1618–1630, 2016.
- A. Borkowska, A. Sielicka-Dudzin, A. Herman-Antosiewicz et al., “Diallyl trisulfide-induced prostate cancer cell death is associated with Akt/PKB dephosphorylation mediated by P-p66shc,” European Journal of Nutrition, vol. 51, no. 7, pp. 817–825, 2012.
- D. V. Chartoumpekis, N. Wakabayashi, and T. W. Kensler, “Keap1/Nrf2 pathway in the frontiers of cancer and non-cancer cell metabolism,” Biochemical Society Transactions, vol. 43, no. 4, pp. 639–644, 2015.
- B. H. Sarmadi and A. Ismail, “Antioxidative peptides from food proteins: a review,” Peptides, vol. 31, no. 10, pp. 1949–1956, 2010.
- J. K. Kundu and Y. J. Surh, “Nrf2-Keap1 signaling as a potential target for chemoprevention of inflammation-associated carcinogenesis,” Pharmaceutical Research, vol. 27, no. 6, pp. 999–1013, 2010.
- B. Perillo, M. Di Donato, A. Pezone et al., “ROS in cancer therapy: the bright side of the moon,” Experimental & Molecular Medicine, vol. 52, no. 2, pp. 192–203, 2020.
- A. H. Kabir, T. Debnath, U. Das et al., “Arbuscular mycorrhizal fungi alleviate Fe-deficiency symptoms in sunflower by increasing iron uptake and its availability along with antioxidant defense,” Plant Physiology and Biochemistry, vol. 150, pp. 254–262, 2020.
- Z. Liu, X. Wang, L. Li, G. Wei, and M. Zhao, “Hydrogen sulfide protects against Paraquat-induced acute liver injury in rats by regulating oxidative stress, mitochondrial function, and inflammation,” Oxidative Medicine and Cellular Longevity, vol. 2020, Article ID 6325378, 16 pages, 2020.
- H. Lei, G. Wang, J. Zhang, and Q. Han, “Inhibiting TrxR suppresses liver cancer by inducing apoptosis and eliciting potent antitumor immunity,” Oncology Reports, vol. 40, no. 6, pp. 3447–3457, 2018.
- X. H. Luo, J. Z. Liu, B. Wang et al., “KLF14 potentiates oxidative adaptation via modulating HO-1 signaling in castrate-resistant prostate cancer,” Endocrine-Related Cancer, vol. 26, no. 1, pp. 181–195, 2019.
- Q. Liu, H. Zhang, L. Smeester et al., “The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel,” BMC Medical Genomics, vol. 3, no. 1, 2010.
- S. Lv, L. Ji, B. Chen et al., “Histone methyltransferase KMT2D sustains prostate carcinogenesis and metastasis via epigenetically activating LIFR and KLF4,” Oncogene, vol. 37, no. 10, pp. 1354–1368, 2018.
- S. Lv, H. Wen, X. Shan et al., “Loss of KMT2D induces prostate cancer ROS-mediated DNA damage by suppressing the enhancer activity and DNA binding of antioxidant transcription factor FOXO3,” Epigenetics, vol. 14, no. 12, pp. 1194–1208, 2019.
- Z. Xu, Y. Zhang, J. Ding et al., “miR-17-3p downregulates mitochondrial antioxidant enzymes and enhances the radiosensitivity of prostate cancer cells,” Molecular Therapy - Nucleic Acids, vol. 13, pp. 64–77, 2018.
- W. Droge, “Free radicals in the physiological control of cell function,” Physiological Reviews, vol. 82, no. 1, pp. 47–95, 2002.
- M. Ruscica, M. Botta, N. Ferri et al., “High Density Lipoproteins Inhibit Oxidative Stress-Induced Prostate Cancer Cell Proliferation,” Scientific Reports, vol. 8, no. 1, p. 2236, 2018.
- A. Barreiro-Alonso, M. Lamas-Maceiras, E. Rodriguez-Belmonte, A. Vizoso-Vazquez, M. Quindos, and M. E. Cerdan, “High mobility group B proteins, their partners, and other redox sensors in ovarian and prostate cancer,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 5845061, 17 pages, 2016.
- D. Ziech, R. Franco, A. Pappa, and M. I. Panayiotidis, “Reactive oxygen species (ROS)--induced genetic and epigenetic alterations in human carcinogenesis,” Mutation Research, vol. 711, no. 1-2, pp. 167–173, 2011.
- T. B. Kryston, A. B. Georgiev, P. Pissis, and A. G. Georgakilas, “Role of oxidative stress and DNA damage in human carcinogenesis,” Mutation Research, vol. 711, no. 1-2, pp. 193–201, 2011.
- L. Khandrika, B. Kumar, S. Koul, P. Maroni, and H. K. Koul, “Oxidative stress in prostate cancer,” Cancer Letters, vol. 282, no. 2, pp. 125–136, 2009.
- K. Block and Y. Gorin, “Aiding and abetting roles of NOX oxidases in cellular transformation,” Nature Reviews. Cancer, vol. 12, no. 9, pp. 627–637, 2012.
- L. Zhou, Y. Yang, D. Tian, and Y. Wang, “Oxidative stress-induced 1, N6-ethenodeoxyadenosine adduct formation contributes to hepatocarcinogenesis,” Oncology Reports, vol. 29, no. 3, pp. 875–884, 2013.
- H. K. Seitz and F. Stickel, “Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress,” Biological Chemistry, vol. 387, no. 4, pp. 349–360, 2006.
- K. I. Leonova, J. Shneyder, M. P. Antoch et al., “A small molecule inhibitor of p53 stimulates amplification of hematopoietic stem cells but does not promote tumor development in mice,” Cell Cycle, vol. 9, no. 7, pp. 1434–1443, 2014.
- D. Yuan, S. Huang, E. Berger et al., “Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS,” Cancer Cell, vol. 31, no. 6, pp. 771–789.e6, 2017.
- F. Weinberg, R. Hamanaka, W. W. Wheaton et al., “Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 19, pp. 8788–8793, 2010.
- U. Weyemi, O. Lagente-Chevallier, M. Boufraqech et al., “ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence,” Oncogene, vol. 31, no. 9, pp. 1117–1129, 2012.
- M. Holl, R. Koziel, G. Schafer et al., “ROS signaling by NADPH oxidase 5 modulates the proliferation and survival of prostate carcinoma cells,” Molecular Carcinogenesis, vol. 55, no. 1, pp. 27–39, 2016.
- K. England and T. G. Cotter, “Direct oxidative modifications of signalling proteins in mammalian cells and their effects on apoptosis,” Redox Report, vol. 10, no. 5, pp. 237–245, 2013.
- Z. Hong, G. Wu, Z. D. Xiang et al., “KDM5C is transcriptionally regulated by BRD4 and promotes castration-resistance prostate cancer cell proliferation by repressing PTEN,” Biomedicine & Pharmacotherapy, vol. 114, p. 108793, 2019.
- Y. Wang, R. Wang, S. Wu et al., “Self-responsive co-delivery system for remodeling tumor intracellular microenvironment to promote PTEN-mediated anti-tumor therapy,” Nanoscale, vol. 12, no. 17, pp. 9392–9403, 2020.
- M. A. Chetram, A. S. Don-Salu-Hewage, and C. V. Hinton, “ROS enhances CXCR4-mediated functions through inactivation of PTEN in prostate cancer cells,” Biochemical and Biophysical Research Communications, vol. 410, no. 2, pp. 195–200, 2011.
- S. Parbin, S. Kar, A. Shilpi et al., “Histone deacetylases: a saga of perturbed acetylation homeostasis in cancer,” The Journal of Histochemistry and Cytochemistry, vol. 62, no. 1, pp. 11–33, 2013.
- S. Kar, D. Sengupta, M. Deb et al., “Expression profiling of DNA methylation-mediated epigenetic gene-silencing factors in breast cancer,” Clinical Epigenetics, vol. 6, no. 1, p. 20, 2014.
- I. Afanas’ev, “New nucleophilic mechanisms of ros-dependent epigenetic modifications: comparison of aging and cancer,” Aging and Disease, vol. 5, no. 1, pp. 52–62, 2014.
- F. J. Rang and J. Boonstra, “Causes and consequences of age-related changes in DNA methylation: a role for ROS?” Biology, vol. 3, no. 2, pp. 403–425, 2014.
- E. Lee, J. Wang, K. Yumoto et al., “DNMT1 regulates epithelial-mesenchymal transition and cancer stem cells, which promotes prostate cancer metastasis,” Neoplasia, vol. 18, no. 9, pp. 553–566, 2016.
- V. Tzelepi, S. Logotheti, E. Efstathiou et al., “Epigenetics and prostate cancer: defining the timing of DNA methyltransferase deregulation during prostate cancer progression,” Pathology, vol. 52, no. 2, pp. 218–227, 2020.
- N. Pradhan, S. Parbin, S. Kar et al., “Epigenetic silencing of genes enhanced by collective role of reactive oxygen species and MAPK signaling downstream ERK/Snail axis: ectopic application of hydrogen peroxide repress CDH1 gene by enhanced DNA methyltransferase activity in human breast cancer,” Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1865, no. 6, pp. 1651–1665, 2019.
- T. Kamiya, A. Goto, E. Kurokawa, H. Hara, and T. Adachi, “Cross talk mechanism among EMT, ROS, and histone acetylation in phorbol ester-treated human breast cancer MCF-7 cells,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 1284372, 11 pages, 2016.
- T. Kouzarides, “Chromatin modifications and their function,” Cell, vol. 128, no. 4, pp. 693–705, 2007.
- L. P. Webber, V. P. Wagner, M. Curra et al., “Hypoacetylation of acetyl-histone H3 (H3K9ac) as marker of poor prognosis in oral cancer,” Histopathology, vol. 71, no. 2, pp. 278–286, 2017.
- J. Ellinger, A. C. Schneider, A. Bachmann, G. Kristiansen, S. C. Muller, and S. Rogenhofer, “Evaluation of global histone acetylation levels in bladder cancer patients,” Anticancer Research, vol. 36, no. 8, pp. 3961–3964, 2016.
- F. Valdes-Mora, C. M. Gould, Y. Colino-Sanguino et al., “Acetylated histone variant H2A.Z is involved in the activation of neo-enhancers in prostate cancer,” Nature Communications, vol. 8, no. 1, p. 1346, 2017.
- K. T. Turpaev, “Reactive oxygen species and regulation of gene expression,” Biochemistry (Mosc), vol. 67, no. 3, pp. 281–292, 2002.
- Z. Culig and M. Puhr, “Interleukin-6: a multifunctional targetable cytokine in human prostate cancer,” Molecular and Cellular Endocrinology, vol. 360, no. 1-2, pp. 52–58, 2012.
- D. J. Waugh and C. Wilson, “The interleukin-8 pathway in cancer,” Clinical Cancer Research, vol. 14, no. 21, pp. 6735–6741, 2008.
- V. T. Baron, R. Pio, Z. Jia, and D. Mercola, “Early Growth Response 3 regulates genes of inflammation and directly activates IL6 and IL8 expression in prostate cancer,” British Journal of Cancer, vol. 112, no. 4, pp. 755–764, 2015.
- G. Thiel, J. Welck, U. Wissenbach, and O. G. Rossler, “Dihydrotestosterone activates AP-1 in LNCaP prostate cancer cells,” The International Journal of Biochemistry & Cell Biology, vol. 110, pp. 9–20, 2019.
- T. Shimura, M. Sasatani, K. Kamiya, H. Kawai, Y. Inaba, and N. Kunugita, “Mitochondrial reactive oxygen species perturb AKT/cyclin D1 cell cycle signaling via oxidative inactivation of PP2A in lowdose irradiated human fibroblasts,” Oncotarget, vol. 7, no. 3, pp. 3559–3570, 2016.
- P. Wang, Y. Zeng, T. Liu et al., “Chloride intracellular channel 1 regulates colon cancer cell migration and invasion through ROS/ERK pathway,” World Journal of Gastroenterology, vol. 20, no. 8, pp. 2071–2078, 2014.
- Y. Shi, F. Nikulenkov, J. Zawacka-Pankau et al., “ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis,” Cell Death and Differentiation, vol. 21, no. 4, pp. 612–623, 2014.
- G. A. Malfa, B. Tomasello, R. Acquaviva et al., “Betula etnensis Raf. (Betulaceae) Extract Induced HO-1 Expression and Ferroptosis Cell Death in Human Colon Cancer Cells,” International Journal of Molecular Sciences, vol. 20, no. 11, p. 2723, 2019.
- G. Yang, H. Yin, F. Lin et al., “Long noncoding RNA TUG1 regulates prostate cancer cell proliferation, invasion and migration via the Nrf2 signaling axis,” Pathology-Research and Practice, vol. 216, no. 4, p. 152851, 2020.
- D. Han, S. Gao, K. Valencia et al., “A novel nonsense mutation in androgen receptor confers resistance to CYP17 inhibitor treatment in prostate cancer,” Oncotarget, vol. 8, no. 4, pp. 6796–6808, 2017.
- K. Fujita and N. Nonomura, “Role of androgen receptor in prostate cancer: a review,” The World Journal of Men's Health, vol. 37, no. 3, pp. 288–295, 2019.
- C. Massard and K. Fizazi, “Targeting continued androgen receptor signaling in prostate cancer,” Clinical Cancer Research, vol. 17, no. 12, pp. 3876–3883, 2011.
- M. H. Tan, J. Li, H. E. Xu, K. Melcher, and E. L. Yong, “Androgen receptor: structure, role in prostate cancer and drug discovery,” Acta Pharmacologica Sinica, vol. 36, no. 1, pp. 3–23, 2015.
- P. Li, S. V. Nicosia, and W. Bai, “Antagonism between PTEN/MMAC1/TEP-1 and androgen receptor in growth and apoptosis of prostatic cancer cells,” The Journal of Biological Chemistry, vol. 276, no. 23, pp. 20444–20450, 2001.
- N. Khurana and S. C. Sikka, “Targeting Crosstalk between Nrf-2, NF-κB and Androgen Receptor Signaling in Prostate Cancer,” Cancers, vol. 10, no. 10, p. 352, 2018.
- I. S. Song, Y. J. Jeong, J. Kim et al., “Pharmacological inhibition of androgen receptor expression induces cell death in prostate cancer cells,” Cellular and Molecular Life Sciences, 2020.
- H. Lilja, D. Ulmert, and A. J. Vickers, “Prostate-specific antigen and prostate cancer: prediction, detection and monitoring,” Nature Reviews Cancer, vol. 8, no. 4, pp. 268–278, 2008.
- A. I. Markowska, F. T. Liu, and N. Panjwani, “Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response,” The Journal of Experimental Medicine, vol. 207, no. 9, pp. 1981–1993, 2010.
- E. S. Antonarakis, “Predicting treatment response in castration-resistant prostate cancer: could androgen receptor variant-7 hold the key?” Expert Review of Anticancer Therapy, vol. 15, no. 2, pp. 143–145, 2014.
- R. Chmelar, G. Buchanan, E. F. Need, W. Tilley, and N. M. Greenberg, “Androgen receptor coregulators and their involvement in the development and progression of prostate cancer,” International Journal of Cancer, vol. 120, no. 4, pp. 719–733, 2007.
- J. Yu, P. Zhou, W. Du et al., “Metabolically stable diphenylamine derivatives suppress androgen receptor and BET protein in prostate cancer,” Biochemical Pharmacology, vol. 177, p. 113946, 2020.
- F. J. Chou, Y. Chen, D. Chen et al., “Preclinical study using androgen receptor (AR) degradation enhancer to increase radiotherapy efficacy via targeting radiation-increased AR to better suppress prostate cancer progression,” eBioMedicine, vol. 40, pp. 504–516, 2019.
- S. Jayakumar, A. Kunwar, S. K. Sandur, B. N. Pandey, and R. C. Chaubey, “Differential response of DU145 and PC3 prostate cancer cells to ionizing radiation: role of reactive oxygen species, GSH and Nrf2 in radiosensitivity,” Biochimica et Biophysica Acta, vol. 1840, no. 1, pp. 485–494, 2014.
- W. Shan, W. Zhong, R. Zhao, and T. D. Oberley, “Thioredoxin 1 as a subcellular biomarker of redox imbalance in human prostate cancer progression,” Free Radical Biology & Medicine, vol. 49, no. 12, pp. 2078–2087, 2010.
- F. Fontana, M. Raimondi, M. Marzagalli et al., “Mitochondrial functional and structural impairment is involved in the antitumor activity of δ-tocotrienol in prostate cancer cells,” Free Radical Biology & Medicine, vol. 160, pp. 376–390, 2020.
- M. Aksel, O. Bozkurt-Girit, and M. D. Bilgin, “Pheophorbide a-mediated Sonodynamic, Photodynamic and Sonophotodynamic Therapies Against Prostate Cancer,” Photodiagnosis and Photodynamic Therapy, vol. 31, article 101909, 2020.
- M. K. Conley-LaComb, A. Saliganan, P. Kandagatla, Y. Q. Chen, M. L. Cher, and S. R. Chinni, “PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling,” Molecular Cancer, vol. 12, no. 1, p. 85, 2013.
- H. Lai, D. Zeng, C. Liu, Q. Zhang, X. Wang, and T. Chen, “Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling,” Biomaterials, vol. 219, p. 119377, 2019.
- G. J. Samaranayake, C. I. Troccoli, M. Huynh et al., “Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer,” Nature Communications, vol. 8, no. 1, p. 1204, 2017.
- M. A. Schultz, S. S. Hagan, A. Datta et al., “Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells,” PLoS One, vol. 9, no. 1, article e87204, 2014.
- T. Mitani, R. Yamaji, Y. Higashimura, N. Harada, Y. Nakano, and H. Inui, “Hypoxia enhances transcriptional activity of androgen receptor through hypoxia-inducible factor-1α in a low androgen environment,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 123, no. 1-2, pp. 58–64, 2011.
- J. Greene, A. M. Baird, O. Casey et al., “Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide,” Scientific Reports, vol. 9, no. 1, p. 10739, 2019.
- M. Kohli, Y. Ho, D. W. Hillman et al., “Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance,” Clinical Cancer Research, vol. 23, no. 16, pp. 4704–4715, 2017.
- K. I. Takayama, “Splicing Factors Have an Essential Role in Prostate Cancer Progression and Androgen Receptor Signaling,” Biomolecules, vol. 9, no. 4, p. 131, 2019.
- Y. He, Y. Luo, D. Zhang et al., “PGK1-mediated cancer progression and drug resistance,” American Journal of Cancer Research, vol. 9, no. 11, pp. 2280–2302, 2019.
- L. C. Bott, N. M. Badders, K. L. Chen et al., “A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy,” Human Molecular Genetics, vol. 25, no. 10, pp. 1979–1989, 2016.
- S. Kumar, S. Kumar, M. Rajendran et al., “Steroids up-regulate p66Shc longevity protein in growth regulation by inhibiting its ubiquitination,” PLoS One, vol. 6, no. 1, article e15942, 2011.
- W. Wu, D. Karelia, K. Pramanik et al., “Phenylbutyl isoselenocyanate induces reactive oxygen species to inhibit androgen receptor and to initiate p53-mediated apoptosis in LNCaP prostate cancer cells,” Molecular Carcinogenesis, vol. 57, no. 8, pp. 1055–1066, 2018.
- H. Xu, Y. Sun, C. P. Huang, B. You, D. Ye, and C. Chang, “Preclinical Study Using ABT263 to Increase Enzalutamide Sensitivity to Suppress Prostate Cancer Progression Via Targeting BCL2/ROS/USP26 Axis Through Altering ARv7 Protein Degradation,” Cancers, vol. 12, no. 4, p. 831, 2020.
- N. Khurana, P. K. Chandra, H. Kim, A. B. Abdel-Mageed, D. Mondal, and S. C. Sikka, “Bardoxolone-Methyl (CDDO-Me) Suppresses Androgen Receptor and Its Splice-Variant AR-V7 and Enhances Efficacy of Enzalutamide in Prostate Cancer Cells,” Antioxidants, vol. 9, no. 1, p. 68, 2020.
- S. M. Ding, A. L. Lu, J. F. Lu et al., “Macrovascular endothelial cells enhance the motility of liver cancer cells by up-regulation of MMP-3, activation of integrin/FAK signaling pathway and induction of non-classical epithelial-mesenchymal transition,” Journal of Cancer, vol. 11, no. 8, pp. 2044–2059, 2020.
- I. Hwang, “Cell-cell communication via extracellular membrane vesicles and its role in the immune response,” Molecules and Cells, vol. 36, no. 2, pp. 105–111, 2013.
- M. Mittelbrunn and F. Sanchez-Madrid, “Intercellular communication: diverse structures for exchange of genetic information,” Nature Reviews. Molecular Cell Biology, vol. 13, no. 5, pp. 328–335, 2012.
- Y. C. Lin, C. C. Chen, W. M. Chen et al., “LPA1/3 signaling mediates tumor lymphangiogenesis through promoting CRT expression in prostate cancer,” Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, vol. 1863, no. 10, pp. 1305–1315, 2018.
- Y. Yu, Q. Zhang, C. Ma et al., “Mesenchymal stem cells recruited by castration-induced inflammation activation accelerate prostate cancer hormone resistance via chemokine ligand 5 secretion,” Stem Cell Research & Therapy, vol. 9, no. 1, p. 242, 2018.
- D. Y. Sun, J. Q. Wu, Z. H. He, M. F. He, and H. B. Sun, “Cancer-associated fibroblast regulate proliferation and migration of prostate cancer cells through TGF-β signaling pathway,” Life Sciences, vol. 235, p. 116791, 2019.
- G. Wang, D. Zhao, D. J. Spring, and R. A. DePinho, “Genetics and biology of prostate cancer,” Genes & Development, vol. 32, no. 17-18, pp. 1105–1140, 2018.
- R. Fu, J. Zhou, R. Wang et al., “Protocatechuic acid-mediated miR-219a-5p activation inhibits the p66shc oxidant pathway to alleviate alcoholic liver injury,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 3527809, 15 pages, 2019.
- N. Sampson, E. Brunner, A. Weber et al., “Inhibition of Nox4-dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal-mediated protumorigenic interactions,” International Journal of Cancer, vol. 143, no. 2, pp. 383–395, 2018.
- A. Costa, Y. Kieffer, A. Scholer-Dahirel et al., “Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer,” Cancer Cell, vol. 33, no. 3, pp. 463–479.e10, 2018.
- H. Cho, Y. Seo, K. M. Loke et al., “Cancer-stimulated CAFs enhance monocyte differentiation and protumoral TAM activation via IL6 and GM-CSF secretion,” Clinical Cancer Research, vol. 24, no. 21, pp. 5407–5421, 2018.
- T. A. Mace, Z. Ameen, A. Collins et al., “Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner,” Cancer Research, vol. 73, no. 10, pp. 3007–3018, 2013.
- K. Ford, C. J. Hanley, M. Mellone et al., “NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors,” Cancer Research, vol. 80, no. 9, pp. 1846–1860, 2020.
- H. Xiang, C. P. Ramil, J. Hai et al., “Cancer-associated fibroblasts promote immunosuppression by inducing ROS-generating monocytic MDSCs in lung squamous cell carcinoma,” Cancer Immunology Research, vol. 8, no. 4, pp. 436–450, 2020.
- A. Calcinotto, C. Spataro, E. Zagato et al., “IL-23 secreted by myeloid cells drives castration-resistant prostate cancer,” Nature, vol. 559, no. 7714, pp. 363–369, 2018.
- S. Gordon, “Alternative activation of macrophages,” Nature Reviews. Immunology, vol. 3, no. 1, pp. 23–35, 2003.
- R. E. Vickman, M. M. Broman, N. A. Lanman et al., “Heterogeneity of human prostate carcinoma-associated fibroblasts implicates a role for subpopulations in myeloid cell recruitment,” Prostate, vol. 80, no. 2, pp. 173–185, 2019.
- J. Escamilla, S. Schokrpur, C. Liu et al., “CSF1 receptor targeting in prostate cancer reverses macrophage-mediated resistance to androgen blockade therapy,” Cancer Research, vol. 75, no. 6, pp. 950–962, 2015.
- J. Mauer, B. Chaurasia, J. Goldau et al., “Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin,” Nature Immunology, vol. 15, no. 5, pp. 423–430, 2014.
- J. Braune, U. Weyer, C. Hobusch et al., “IL-6 regulates M2 polarization and local proliferation of adipose tissue macrophages in obesity,” Journal of Immunology, vol. 198, no. 7, pp. 2927–2934, 2017.
- M. S. Baig, A. Roy, S. Rajpoot et al., “Tumor-derived exosomes in the regulation of macrophage polarization,” Inflammation Research, vol. 69, no. 5, pp. 435–451, 2020.
- A. Erlandsson, J. Carlsson, M. Lundholm et al., “M2 macrophages and regulatory T cells in lethal prostate cancer,” Prostate, vol. 79, no. 4, pp. 363–369, 2019.
- K. Roy, Y. Wu, J. L. Meitzler et al., “NADPH oxidases and cancer,” Clinical Science (London, England), vol. 128, no. 12, pp. 863–875, 2015.
- R. Huang, S. Wang, N. Wang et al., “CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling,” Cell Death & Disease, vol. 11, no. 4, p. 234, 2020.
- H. Y. Tan, N. Wang, S. Li, M. Hong, X. Wang, and Y. Feng, “The reactive oxygen species in macrophage polarization: reflecting its dual role in progression and treatment of human diseases,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 2795090, 16 pages, 2016.
- L. Luput, E. Licarete, A. Sesarman, L. Patras, M. C. Alupei, and M. Banciu, “Tumor-associated macrophages favor C26 murine colon carcinoma cell proliferation in an oxidative stress-dependent manner,” Oncology Reports, vol. 37, no. 4, pp. 2472–2480, 2017.
- B. Griess, S. Mir, K. Datta, and M. Teoh-Fitzgerald, “Scavenging reactive oxygen species selectively inhibits M2 macrophage polarization and their pro-tumorigenic function in part, via Stat3 suppression,” Free Radical Biology & Medicine, vol. 147, pp. 48–60, 2020.
- R. Feng, Y. Morine, T. Ikemoto et al., “Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction,” Cell Commun Signal, vol. 16, no. 1, p. 54, 2018.
- S. H. Lee, J. S. Park, J. K. Byun et al., “Erratum: Corrigendum: PTEN ameliorates autoimmune arthritis through down-regulating STAT3 activation with reciprocal balance of Th17 and Tregs,” Scientific Reports, vol. 7, no. 1, 2017.
- T. A. Curran, R. B. Jalili, A. Farrokhi, and A. Ghahary, “IDO expressing fibroblasts promote the expansion of antigen specific regulatory T cells,” Immunobiology, vol. 219, no. 1, pp. 17–24, 2014.
- I. Mellman, G. Coukos, and G. Dranoff, “Cancer immunotherapy comes of age,” Nature, vol. 480, no. 7378, pp. 480–489, 2011.
- S. L. Topalian, J. M. Taube, R. A. Anders, and D. M. Pardoll, “Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy,” Nature Reviews. Cancer, vol. 16, no. 5, pp. 275–287, 2016.
- N. Ness, S. Andersen, A. Valkov et al., “Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure-free survival in prostate cancer,” Prostate, vol. 74, no. 14, pp. 1452–1461, 2014.
- M. Gururajan, E. M. Posadas, and L. W. Chung, “Future perspectives of prostate cancer therapy,” Translational Andrology and Urology, vol. 1, no. 1, pp. 19–32, 2012.
- J. F. Grosso, C. C. Kelleher, T. J. Harris et al., “LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems,” The Journal of Clinical Investigation, vol. 117, no. 11, pp. 3383–3392, 2007.
- C. Bailly, “Regulation of PD-L1 expression on cancer cells with ROS-modulating drugs,” Life Sciences, vol. 246, p. 117403, 2020.
- S. S. Wang, G. Chen, S. H. Li et al., “Identification and validation of an individualized autophagy-clinical prognostic index in bladder cancer patients,” Oncotargets and Therapy, vol. Volume 12, pp. 3695–3712, 2019.
- C. G. Towers and A. Thorburn, “Therapeutic targeting of autophagy,” eBioMedicine, vol. 14, pp. 15–23, 2016.
- S. Luo, L. Shao, Z. Chen, D. Hu, L. Jiang, and W. Tang, “NPRL2 promotes docetaxel chemoresistance in castration resistant prostate cancer cells by regulating autophagy through the mTOR pathway,” Experimental Cell Research, vol. 390, no. 2, article 111981, 2020.
- J. Nassour, R. Radford, A. Correia et al., “Autophagic cell death restricts chromosomal instability during replicative crisis,” Nature, vol. 565, no. 7741, pp. 659–663, 2019.
- R. Mathew, C. M. Karp, B. Beaudoin et al., “Autophagy suppresses tumorigenesis through elimination of p62,” Cell, vol. 137, no. 6, pp. 1062–1075, 2009.
- F. Janku, D. J. McConkey, D. S. Hong, and R. Kurzrock, “Autophagy as a target for anticancer therapy,” Nature Reviews. Clinical Oncology, vol. 8, no. 9, pp. 528–539, 2011.
- E. White, “Deconvoluting the context-dependent role for autophagy in cancer,” Nature Reviews. Cancer, vol. 12, no. 6, pp. 401–410, 2012.
- X. Sui, N. Kong, L. Ye et al., “p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents,” Cancer Letters, vol. 344, no. 2, pp. 174–179, 2014.
- J. Sha, Q. Han, C. Chi et al., “Upregulated KDM4B promotes prostate cancer cell proliferation by activating autophagy,” Journal of Cellular Physiology, vol. 235, no. 3, pp. 2129–2138, 2020.
- A. M. Blessing, K. Rajapakshe, L. Reddy Bollu et al., “Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression,” Autophagy, vol. 13, no. 3, pp. 506–521, 2017.
- Y. Shi, J. J. Han, J. B. Tennakoon et al., “Androgens promote prostate cancer cell growth through induction of autophagy,” Molecular Endocrinology, vol. 27, no. 2, pp. 280–295, 2013.
- R. Scherz-Shouval, E. Shvets, E. Fass, H. Shorer, L. Gil, and Z. Elazar, “Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4,” The EMBO Journal, vol. 26, no. 7, pp. 1749–1760, 2007.
- S. B. Gibson, “A matter of balance between life and death: targeting reactive oxygen species (ROS)-induced autophagy for cancer therapy,” Autophagy, vol. 6, no. 7, pp. 835–837, 2014.
- A. Alexander, S. L. Cai, J. Kim et al., “ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 9, pp. 4153–4158, 2010.
- G. Jiang, X. Liang, Y. Huang et al., “p62 promotes proliferation, apoptosis‑resistance and invasion of prostate cancer cells through the Keap1/Nrf2/ARE axis,” Oncology Reports, vol. 43, no. 5, pp. 1547–1557, 2020.
- Y. Zhao, T. Qu, P. Wang et al., “Unravelling the relationship between macroautophagy and mitochondrial ROS in cancer therapy,” Apoptosis, vol. 21, no. 5, pp. 517–531, 2016.
- K. Y. Kim, S. H. Kim, S. N. Yu et al., “Lasalocid induces cytotoxic apoptosis and cytoprotective autophagy through reactive oxygen species in human prostate cancer PC-3 cells,” Biomedicine & Pharmacotherapy, vol. 88, pp. 1016–1024, 2017.
- S. H. Kim, K. Y. Kim, S. G. Park et al., “Mitochondrial ROS activates ERK/autophagy pathway as a protected mechanism against deoxypodophyllotoxin-induced apoptosis,” Oncotarget, vol. 8, no. 67, pp. 111581–111596, 2017.
- Y. Chen, W. Zhang, X. Guo, J. Ren, and A. Gao, “The crosstalk between autophagy and apoptosis was mediated by phosphorylation of Bcl-2 and beclin1 in benzene-induced hematotoxicity,” Cell Death & Disease, vol. 10, no. 10, p. 772, 2019.
- J. Wang, X. Tan, Q. Yang et al., “Inhibition of autophagy promotes apoptosis and enhances anticancer efficacy of adriamycin via augmented ROS generation in prostate cancer cells,” The International Journal of Biochemistry & Cell Biology, vol. 77, no. Part A, pp. 80–90, 2016.
- N. Chen and V. Karantza-Wadsworth, “Role and regulation of autophagy in cancer,” Biochimica et Biophysica Acta, vol. 1793, no. 9, pp. 1516–1523, 2009.
- B. Li, P. Zhou, K. Xu et al., “Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma,” International Journal of Biological Sciences, vol. 16, no. 1, pp. 74–84, 2020.
- A. K. De, R. Muthiyan, S. Mondal et al., “A Natural Quinazoline Derivative from Marine Sponge Hyrtios erectus Induces Apoptosis of Breast Cancer Cells via ROS Production and Intrinsic or Extrinsic Apoptosis Pathways,” Marine Drugs, vol. 17, no. 12, p. 658, 2019.
- Q. P. Liang, T. Q. Xu, B. L. Liu et al., “Sasanquasaponin ΙΙΙ from Schima crenata Korth induces autophagy through Akt/mTOR/p70S6K pathway and promotes apoptosis in human melanoma A375 cells,” Phytomedicine, vol. 58, p. 152769, 2019.
- S. Yodkeeree, B. Sung, P. Limtrakul, and B. B. Aggarwal, “Zerumbone enhances TRAIL-induced apoptosis through the induction of death receptors in human colon cancer cells: evidence for an essential role of reactive oxygen species,” Cancer Research, vol. 69, no. 16, pp. 6581–6589, 2009.
- S. Wu, Y. Yang, F. Li et al., “Chelerythrine induced cell death through ROS-dependent ER stress in human prostate cancer cells,” Oncotargets and Therapy, vol. Volume 11, pp. 2593–2601, 2018.
- S. Sabnam, H. Rizwan, S. Pal, and A. Pal, “CEES-induced ROS accumulation regulates mitochondrial complications and inflammatory response in keratinocytes,” Chemico-Biological Interactions, vol. 321, p. 109031, 2020.
- J. L. Martindale and N. J. Holbrook, “Cellular response to oxidative stress: signaling for suicide and survival,” Journal of Cellular Physiology, vol. 192, no. 1, pp. 1–15, 2002.
- N. Abdelmageed, S. A. F. Morad, A. A. Elghoneimy et al., “Oleanolic acid methyl ester, a novel cytotoxic mitocan, induces cell cycle arrest and ROS-mediated cell death in castration-resistant prostate cancer PC-3 cells,” Biomedicine & Pharmacotherapy, vol. 96, pp. 417–425, 2017.
- J. Tao, G. Sun, Q. Li et al., “KIF15 promotes the evolution of gastric cancer cells through inhibition of reactive oxygen species-mediated apoptosis,” Journal of Cellular Physiology, 2020.
- Q. Chen and E. J. Lesnefsky, “Depletion of cardiolipin and cytochrome c during ischemia increases hydrogen peroxide production from the electron transport chain,” Free Radical Biology & Medicine, vol. 40, no. 6, pp. 976–982, 2006.
- A. Ashkenazi and V. M. Dixit, “Apoptosis control by death and decoy receptors,” Current Opinion in Cell Biology, vol. 11, no. 2, pp. 255–260, 1999.
- J. D. Malhotra and R. J. Kaufman, “Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?” Antioxidants & Redox Signaling, vol. 9, no. 12, pp. 2277–2294, 2007.
- W. Chen, P. Li, Y. Liu et al., “Isoalantolactone induces apoptosis through ROS-mediated ER stress and inhibition of STAT3 in prostate cancer cells,” Journal of Experimental & Clinical Cancer Research, vol. 37, no. 1, p. 309, 2018.
- Y. Yang, X. Luo, M. Yasheng, J. Zhao, J. Li, and J. Li, “Ergosterol Peroxide from Pleurotus Ferulae Inhibits Gastrointestinal Tumor Cell Growth through Induction of Apoptosis Via Reactive Oxygen Species and Endoplasmic Reticulum Stress,” Food & Function, vol. 11, no. 5, pp. 4171–4184, 2020.
- A. Zhao, Z. Zhang, Y. Zhou et al., “β-Elemonic acid inhibits the growth of human Osteosarcoma through endoplasmic reticulum (ER) stress-mediated PERK/eIF2α/ATF4/CHOP activation and Wnt/β-catenin signal suppression,” Phytomedicine, vol. 69, p. 153183, 2020.
- H. D. Cho, J. H. Lee, K. D. Moon, K. H. Park, M. K. Lee, and K. I. Seo, “Auriculasin-induced ROS causes prostate cancer cell death via induction of apoptosis,” Food and Chemical Toxicology, vol. 111, pp. 660–669, 2018.
- X. L. Sun, X. W. Zhang, H. J. Zhai, D. Zhang, and S. Y. Ma, “Magnoflorine inhibits human gastric cancer progression by inducing autophagy, apoptosis and cell cycle arrest by JNK activation regulated by ROS,” Biomedicine & Pharmacotherapy, vol. 125, p. 109118, 2020.
- L. J. Bailey, T. J. Cluett, A. Reyes et al., “Mice expressing an error-prone DNA polymerase in mitochondria display elevated replication pausing and chromosomal breakage at fragile sites of mitochondrial DNA,” Nucleic Acids Research, vol. 37, no. 7, pp. 2327–2335, 2009.
- S. A. Zakki, J. S. Muhammad, J. L. Li et al., “Melatonin triggers the anticancer potential of phenylarsine oxide via induction of apoptosis through ROS generation and JNK activation,” Metallomics, vol. 12, no. 3, pp. 396–407, 2020.
- E. White and R. S. DiPaola, “The double-edged sword of autophagy modulation in cancer,” Clinical Cancer Research, vol. 15, no. 17, pp. 5308–5316, 2009.
- D. You, Y. Kim, M. J. Jang et al., “KML001 Induces Apoptosis and Autophagic Cell Death in Prostate Cancer Cells via Oxidative Stress Pathway,” PLoS One, vol. 10, no. 9, article e0137589, 2015.
- P. Mattiolo, A. Barbero-Farran, V. J. Yuste, J. Boix, and J. Ribas, “2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53,” Biochemical Pharmacology, vol. 91, no. 3, pp. 301–311, 2014.
- T. Numata, K. Sato-Numata, and Y. Okada, “TRPM7 is involved in acid-induced necrotic cell death in a manner sensitive to progesterone in human cervical cancer cells,” Physiological Reports, vol. 7, no. 13, article e14157, 2019.
- S. Ganapathy-Kanniappan and J. F. Geschwind, “Tumor glycolysis as a target for cancer therapy: progress and prospects,” Molecular Cancer, vol. 12, no. 1, p. 152, 2013.
- B. S. Dwarakanath, “Cytotoxicity,radiosensitization, and chemosensitization of tumor cells by 2-deoxy-D-glucoseIn vitro,” Journal of Cancer Research and Therapeutics, vol. 5, no. 9, article 55137, pp. 27–31, 2009.
- L. Wang, J. Wang, H. Xiong et al., “Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer,” eBioMedicine, vol. 7, pp. 50–61, 2016.
- J. Cui, M. Yan, X. Liu et al., “Inorganic selenium induces nonapoptotic programmed cell death in PC-3 prostate cancer cells associated with inhibition of glycolysis,” Journal of Agricultural and Food Chemistry, vol. 67, no. 38, pp. 10637–10645, 2019.
- X. Liu, Y. Zhang, H. Gao et al., “Induction of an MLKL mediated non-canonical necroptosis through reactive oxygen species by tanshinol a in lung cancer cells,” Biochemical Pharmacology, vol. 171, p. 113684, 2020.
- R. Weinlich, A. Oberst, H. M. Beere, and D. R. Green, “Necroptosis in development, inflammation and disease,” Nature Reviews. Molecular Cell Biology, vol. 18, no. 2, pp. 127–136, 2017.
- M. Conrad, J. P. Angeli, P. Vandenabeele, and B. R. Stockwell, “Regulated necrosis: disease relevance and therapeutic opportunities,” Nature Reviews. Drug Discovery, vol. 15, no. 5, pp. 348–366, 2016.
- M. Pasparakis and P. Vandenabeele, “Necroptosis and its role in inflammation,” Nature, vol. 517, no. 7534, pp. 311–320, 2015.
- S. K. Chiang, S. E. Chen, and L. C. Chang, “A Dual Role of Heme Oxygenase-1 in Cancer Cells,” International Journal of Molecular Sciences, vol. 20, no. 1, p. 39, 2019.
- T. C. Chen, J. Y. Chuang, C. Y. Ko et al., “AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-Mediated redox homeostasis,” Redox Biology, vol. 30, p. 101413, 2020.
- P. Dolara, E. Bigagli, and A. Collins, “Antioxidant vitamins and mineral supplementation, life span expansion and cancer incidence: a critical commentary,” European Journal of Nutrition, vol. 51, no. 7, pp. 769–781, 2012.
- S. M. Lippman, P. J. Goodman, E. A. Klein et al., “Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT),” Journal of the National Cancer Institute, vol. 97, no. 2, pp. 94–102, 2005.
- E. A. Klein, I. M. Thompson Jr., C. M. Tangen et al., “Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT),” JAMA, vol. 306, no. 14, pp. 1549–1556, 2011.
- M. S. Stratton, A. M. Algotar, J. Ranger-Moore et al., “Oral selenium supplementation has no effect on prostate-specific antigen velocity in men undergoing active surveillance for localized prostate cancer,” Cancer Prevention Research (Philadelphia, Pa.), vol. 3, no. 8, pp. 1035–1043, 2010.
- W. B. Grant, “Review of recent advances in understanding the role of vitamin D in reducing cancer risk: breast, colorectal, prostate, and overall cancer,” Anticancer Research, vol. 40, no. 1, pp. 491–499, 2019.
- M. Shiota, A. Yokomizo, and S. Naito, “Oxidative stress and androgen receptor signaling in the development and progression of castration-resistant prostate cancer,” Free Radical Biology & Medicine, vol. 51, no. 7, pp. 1320–1328, 2011.
- J. L. Watters, M. H. Gail, S. J. Weinstein, J. Virtamo, and D. Albanes, “Associations between alpha-tocopherol, beta-carotene, and retinol and prostate cancer survival,” Cancer Research, vol. 69, no. 9, pp. 3833–3841, 2009.
- H. A. Beydoun, M. R. Shroff, R. Mohan, and M. A. Beydoun, “Associations of serum vitamin A and carotenoid levels with markers of prostate cancer detection among US men,” Cancer Causes & Control, vol. 22, no. 11, pp. 1483–1495, 2011.
- S. O. Antwi, S. E. Steck, H. Zhang et al., “Plasma carotenoids and tocopherols in relation to prostate-specific antigen (PSA) levels among men with biochemical recurrence of prostate cancer,” Cancer Epidemiology, vol. 39, no. 5, pp. 752–762, 2015.
- O. Kucuk, F. H. Sarkar, W. Sakr et al., “Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy,” Cancer Epidemiology, Biomarkers & Prevention, vol. 10, no. 8, pp. 861–868, 2001.
- T. E. Newsom-Davis, L. M. Kenny, S. Ngan, J. King, and J. Waxman, “The promiscuous receptor,” BJU International, vol. 104, no. 9, pp. 1204–1207, 2009.
- T. M. Beer, C. W. Ryan, P. M. Venner et al., “Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators,” Journal of Clinical Oncology, vol. 25, no. 6, pp. 669–674, 2007.
- E. Lubos, J. Loscalzo, and D. E. Handy, “Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities,” Antioxidants & Redox Signaling, vol. 15, no. 7, pp. 1957–1997, 2011.
- Z. Cui, D. Liu, C. Liu, and G. Liu, “Serum selenium levels and prostate cancer risk: A MOOSE-compliant meta-analysis,” Medicine, vol. 96, no. 5, article e5944, 2017.
- N. E. Allen, R. C. Travis, P. N. Appleby et al., “Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies,” JNCI: Journal of the National Cancer Institute, vol. 108, no. 11, 2016.
- D. D. Marreiro, K. J. Cruz, J. B. Morais, J. B. Beserra, J. S. Severo, and A. R. de Oliveira, “Zinc and Oxidative Stress: Current Mechanisms,” Antioxidants, vol. 6, no. 2, p. 24, 2017.
- M. M. Epstein, J. L. Kasperzyk, O. Andren et al., “Dietary zinc and prostate cancer survival in a Swedish cohort,” The American Journal of Clinical Nutrition, vol. 93, no. 3, pp. 586–593, 2011.
- G. G. Hillman, Y. Wang, O. Kucuk et al., “Genistein potentiates inhibition of tumor growth by radiation in a prostate cancer orthotopic model,” Molecular Cancer Therapeutics, vol. 3, no. 10, pp. 1271–1279, 2004.
- J. J. Raffoul, S. Banerjee, M. Che et al., “Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model,” International Journal of Cancer, vol. 120, no. 11, pp. 2491–2498, 2007.
- S. Bettuzzi, M. Brausi, F. Rizzi, G. Castagnetti, G. Peracchia, and A. Corti, “Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study,” Cancer Research, vol. 66, no. 2, pp. 1234–1240, 2006.
- N. B. Kumar, J. Pow-Sang, P. E. Spiess et al., “Randomized, placebo-controlled trial evaluating the safety of one-year administration of green tea catechins,” Oncotarget, vol. 7, no. 43, pp. 70794–70802, 2016.
- M. A. Valentovic, “Evaluation of resveratrol in cancer patients and experimental models,” Advances in Cancer Research, vol. 137, pp. 171–188, 2018.
Copyright © 2020 Chenglin Han et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.