The Oncogenic Functions of Nicotinic Acetylcholine Receptors

Zhao, Yue

doi:https://doi.org/10.1155/2016/9650481

Journal of Oncology

On this page

Abstract Introduction References Copyright Related Articles

Review Article | Open Access

Volume 2016 | Article ID 9650481 | https://doi.org/10.1155/2016/9650481

The Oncogenic Functions of Nicotinic Acetylcholine Receptors

Yue Zhao¹

Academic Editor: Kalpesh Jani

Received01 Sept 2015

Revised05 Nov 2015

Accepted16 Nov 2015

Published14 Feb 2016

Abstract

Nicotinic acetylcholine receptors (nAChRs) are ion channels that are expressed in the cell membrane of all mammalian cells, including cancer cells. Recent findings suggest that nAChRs not only mediate nicotine addiction in the brain but also contribute to the development and progression of cancers directly induced by nicotine and its derived carcinogenic nitrosamines whereas deregulation of the nAChRs is observed in many cancers, and genome-wide association studies (GWAS) indicate that SNPs nAChRs associate with risks of lung cancers and nicotine addiction. Emerging evidences suggest nAChRs are posited at the central regulatory loops of numerous cell growth and prosurvival signal pathways and also mediate the synthesis and release of stimulatory and inhibitory neurotransmitters induced by their agonists. Thus nAChRs mediated cell signaling plays an important role in stimulating the growth and angiogenic and neurogenic factors and mediating oncogenic signal transduction during cancer development in a cell type specific manner. In this review, we provide an integrated view of nAChRs signaling in cancer, heightening on the oncogenic properties of nAChRs that may be targeted for cancer treatment.

1. Introduction

The nicotinic acetylcholine receptors (nAChRs) are of a family of ligands gated ion channels that are expressed in the cell membrane of all mammalian cells, including cancer cells [1]. In the nervous system nAChRs have high permeability to calcium, modulated by the extracellular calcium concentrations, phosphorylated by calcium-dependent serine/threonine kinases to regulate the release and activation of neuronal transmitters [2–5]. nAChRs are known to play several important roles involved in learning and cognition through regulating of synaptic plasticity, neuronal growth, differentiation, and survival [6]. The discovery of their expression on nonneuronal cells implicates their broad biological functions involved in cell proliferation, apoptosis, migration, and signal transduction. Recent findings suggest the imbalanced expressions of different subtypes of nAChRs in the cells contribute to the pathogenesis of diseases such as cancer [7].

Cigarette smoking or environmental tobacco smoke is an important risk factor for many types of cancers, including lung cancer, oral cancer, laryngeal cancer, oropharyngeal/hypopharyngeal caner, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, bladder cancer, renal cancer, cervical carcinoma, myeloid leukaemia, and colorectal cancer [8]. Among the carcinogens presented in tobacco, nicotine acts on nAChRs in the central nervous system (CNS) and causes addiction to smoke [9]. And two of its metabolites, namely, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN), bind to nicotinic receptor with much higher affinity than that of nicotine [7]. Recent studies indicated nicotine is able to induce cancer directly via promoting proliferation, inhibiting apoptosis of cancer cells, and stimulating tumor angiogenesis. These findings suggest that nAChRs are the central regulatory module of multiple downstream oncogenic signaling pathways in mediating the cellular responses of nicotine and its derivatives [8]. And nAChRs mediated effects of nicotine function in coalition with the mutagenic effects of the cancerogenic nitrosamine derivatives and reactive oxygen species activated by intracellular nicotine to promote tumor development and progression in tobacco related cancers.

The nAChRs can either be composed of five identical α7, α8, or α9 subunits (homomeric nAChRs) or consist of combinations of α2–α6 or α10 subunits with β2–β4 subunits (heteromeric nAChRs). α7-nAChR and α4β2-nAChR are the evolutionarily oldest nAChRs predominantly expressed in the mammalian brain [10]. α7-nAChR is selective for Ca2+ and other nAChRs allowing the influx of different cations (Na+, K+, and Ca2+) [11, 12]. α7-nAChR is the most growth stimulatory nAChR in cancer cells, whereas α4β2-nAChR is the growth inhibitory receptor. Under normal physiological conditions, nicotine binds to α4β2-nAChR with higher affinity than α7-nAChRs. However, in smokers chronic exposure to nicotine or nicotine-derived carcinogenic nitrosamines leads to the upregulation of all nAChRs and long-term inactivation (or desensitization) of the 2α4β-nAChR [11, 13]; in contrast, the sensitivity of α7-nAChR remains unchanged [13]. Thus chronic exposure to nicotine causes selective activation of the cancer stimulatory nAChRs in the cell (Figure 1).

The affinity of NNK for α7-nAChR is 1,300 times higher than that of nicotine, whereas the affinity of NNN for heteromeric α–β nAChRs is 5,000 times higher than that of nicotine [14, 15]. Thus NNK and NNN can cause displacement of nicotine from these receptors as a result of their higher affinity for nAChRs. Therefore nitrosamines may cause many of the cardiovascular, neuropsychological, and cancer-stimulating effects similar to nicotine. Thus, nicotine, NNK, and NNN bind to nAChRs and other receptors, leading to activation of the serine/threonine kinase AKT, protein kinase A (PKA), and other factors [16, 17].

Based upon recent discoveries in the field, an increasing body of evidence suggests the positive correlations between nAChRs signaling and cancer incidences related to cigarette smoking. Particularly, lung cancers, pancreatic cancers, and esophageal cancers are among the most commonly induced cancers triggered by cigarette smoking and nAChR signaling [8]. In this review we have special focus on the genetic predisposition and molecular pathogenesis of cancers originated from these three organs in related nAChRs.

2. Genetic Variants of nAChRs in Association with Cancer

Single nucleotide polymorphisms (SNPs) of the chromosome 15q25 region, which contains α5-α3-β4 nAChR gene cluster (CHRNA5-CHRNA3-CHRNB4), is frequently associated with nicotine- (tobacco-) dependence, chronic obstructive pulmonary disease (COPD), and lung cancer in genome-wide association studies (GWAS) [18]. The association of the SNPs of 15q25 genomic region with COPD and lung cancer could mediate by the combined effects of the oncogenic nAChR signaling and the neurological effects of nicotine addiction. Among these SNPs rs16969968 in CHRNA5, rs1051730 in CHRNA3, and rs8034191 are the most studied three SNPs of the region [18, 19]. CHRNA3 and CHRNA5 are arranged in a tail-to-tail configuration on the opposite strand of the DNA, and the two variants rs1051730 and rs16969968 are in a complete linkage disequilibrium [ in samples of Europeans/Caucasians]. Similarly rs1051370 is in strong linkage disequilibrium with rs8034191; thus some studies report the results for rs1051370 only. Notably, Chen et al. reported rs1051730 is associated with larger tumor size at diagnosis of squamous cell carcinoma. rs16969968 is a G-to-A [aspartic acid- (D-) to-asparagine (N)] missense variant at amino acid position 398 of CHRNA5 [α5 (Asn398) D398N] [20]. And 398N is less potent than the variant 398D in protecting cells against the nicotine α7-nAChR mediated signaling making cells more susceptible to proliferation and migration [21]. Consistently, risk allele D-Asparagine is observed to reduce the function of α4β2α5-nAChR [18].

Alternatively, polymorphisms in linkage disequilibrium with rs16969968 may modulate the expression of CHRNA5 [22, 23]. Thus the expression of functional (α3β2)2α5-nAChRS may play an important role in regulating the homeostasis and integrity of bronchial mucosa under physical, chemical, and immunological damage. Depending on the balanced regulation of the nAChRs, bronchial mucosa may undergo repair and recovery or give rise to precancerous lesion or hyperplasia when these receptors are deregulated. Moreover, NKK induced bronchial cell proliferation and the susceptibility to the tumorigenic transformation were reported to associate with different variants of human α9-nAChR subunit protein (S442 as the most frequent) [24]. Thus polymorphisms in CHRNA5-CHRNA3-CHRNB4 gene cluster may modulate the dynamics of the normal bronchial epithelium under stress conditions to influence cancer risks [25]. Similarly, these SNPs associated with varied activity of nAChRs may associate with enhanced invasiveness and metastatic capacity. Besides, the effects of the 15q25 polymorphism may impact on the neural behavioral effects on addiction to nicotine, resulting in an increased tobacco consumption, and so forth [26].

Interestingly Wu et al. reported rs8034191, rs1051730, and rs16969968 identified in previous GWAS are extremely rare in Asians, whereas they have identified four novel SNPs that were associated with significantly increased lung cancer risk and smoking behavior in Chinese population [27]. Particularly they have identified that rs6495309T>C considerably influenced the CHRNA3 promoter activity, leading to higher α3-nAChR protein level and an increased risk of lung cancer. This seemingly contradictory observation could be explained as upregulation of (α3β2)2α5-nAChR in brain may dampen the nicotine responses mediated by α7-nAChR and consequently leads to reduced dopamine release upon nicotine induction [26]. Thus individuals with rs6495309C allele may need to consume more nicotine to reach the addictive neurological effects, leading to higher levels of exposure to smoking.

3. The Oncogenic Effects of Neurotransmitters Mediated by nAChRs

Stress neurotransmitters such as dopamine can stimulate the growth of cancer cells in vitro, which is in accord with nAChRs’ role in regulating the release and synthesis of these neurotransmitters in vivo [13]. The effects are partly due to the facts that growth of nerve endings into the tumor microenvironment (neurogenesis) [28, 29] is necessary for the development of many cancers. The process is triggered by neurotrophic factors released from tumor cells to promote the nerve fibres growth into tumor tissues [30]. Consistently, α7-nAChR can promote neurogenesis by stimulating glutamate production whereas α4β2-nAChR can regulate neurogenesis by regulating Gamma-Amino Butyric Acid (GABA) synthesis and release [31, 32]. More importantly, the autocrine neurotransmitters of the catecholamine family play important roles in the carcinogenic pathways regulated by nAChRs. Thus under physiological conditions other risk factors also activate nAChRs to promote cancers in the body, such as psychological stress, and also activate the neuronal pathway through the activation of nAChRs and beta-adrenergic receptors [33].

Similarly NNK can stimulate the growth and migration of small airway epithelial cells through activation of β-adrenergic receptor which further transactivates EGFR through cAMP signaling [34–36]. β-adrenergic agonists such as adrenaline and noradrenaline triggered by nAChRs signaling are responsible for the development pulmonary adenocarcinomas (PACs). And adrenaline treated hamsters showed with significantly increased tumor growth in the NNK induced small-airway-derived PAC model [29]. Similarly noradrenaline plays an important role in promoting the growth of gastrointestinal cancer; it can mediate nicotine signaling through activation of ERK1-ERK2, cyclooxygenase 2 (COX2), prostaglandin E2 (PGE2), and VEGF [16, 37, 38]. Consistently, increased synthesis and releasing of noradrenaline and adrenaline are observed in colon cancer cells by nicotine treatment in vitro, an effect that is blocked by α7-nAChR antagonist [39]. Thus, the β-adrenergic signaling, transactivation of the EGFR, and releasing of EGF are the major contributors to the effects of tumor growth and angiogenesis mediated by nAChRs in colon cancer. Such an effect of nAChR signaling is also observed in many other types of cancers; for instance, the proliferation of mesothelioma cells is stimulated by nicotine through activation of the ERK1-ERK2 signaling cascade and nicotine also inhibits the apoptosis of the cell through activation of NF-κB and phosphorylation of BAD [40]. In bladder cancer cells ERK1-ERK2 as well as STAT3 is also activated by nicotine through nAChRs and β-adrenergic receptors [41].

Suppressive neurotransmitters such as GABA also played a role in regulating cancer cell, and they are synthesized and released by cancer cells in an autocrine fashion. Researches indicated NNK can cause the decreased GABA level in PAC cells and further leads to decreased GABA dependent migration of PAC cells in vitro [42]. Desensitization of α4β2-nAChR is the major cause for decreased release of GABA in smokers and NNK treated hamsters [11, 13, 42]. Consistently, the RNA level of α4-nAChR has been observed to be significantly lower in PAC tissues than that of normal lung tissues [43]. Recent studies indicate suppressive neurotransmitter GABA can inhibit adrenaline induced migration of many types of cancer including colon cancer, prostate cancer, and breast cancer [44]. Joseph et al. reported the tumor suppressor function of GABA in lung adenocarcinoma [43]; similarly GABA can inhibit Gαi-mediated inhibition of adenylyl cyclase and further leads to the inhibition of isoproterenol induced DNA synthesis and migration [45]. These findings are in accord with the association between increased releases of stress neurotransmitters caused by smoking and increased risk of PAC, which is caused by upregulation of α7-nAChR and a concomitant desensitization of α4β2-nAChR induced by smoking.

4. nAChRs in Regulating Tumor Angiogenesis

The pathological angiogenesis of tumor growth and metastasis induced by nicotine has been firstly reported by Heeschen et al. [46]. The proliferation of Lewis lung cancer cells which do not have functional nAChRs was not stimulated by nicotine in vitro. In contrast, accelerated tumor growth was observed after systemic administration of nicotine in xenograft mouse model [46]. And a 5-fold increase of capillary density in the tumor nodules was observed after nicotine administration. These findings suggest nicotine promotes tumor angiogenesis rather than affecting tumor cell proliferation directly in the Lewis lung cancer model. Later work showed second-hand smoke increased tumor angiogenesis and tumor growth, an effect that is associated with elevated plasma VEGF in the Lewis lung cancer model [47]. Consistently, increased endothelial progenitor cells were recruited to the ischemic sites in mice after nicotine administration [48]. In vitro treatment of 10 nM nicotine to human endothelial progenitor cells increased the viability, migratory, and adhesive and vasculogenesis ability of these cells [49]. nAChRs antagonists mecamylamine and α-bungarotoxin can abolish the effect of nicotine on human endothelial progenitors [50].

Cholinergic angiogenesis is mainly mediated by α7-nAChR, which is predominantly expressed in the endothelial cell [50]. Other nAChRs modulate cholinergic angiogenesis through interacting with α7-nAChR. Notably, hypoxia can induce upregulation of α7-nAChR in endothelial cells. And ischemic hindlimb of the mouse expressed increased α7-nAChRs [50]. Consistently α7-nAChR antagonist α-bungarotoxin can suppress the increased endothelial cell migration, proliferation, and tube formation induced by nicotine in vitro. And the angiogenesis effects of nicotine are blunted in mice deficient with α7-nAChR [50]. Moreover, the effect of α7-nAChR on angiogenesis is further demonstrated by the α7-nAChR antagonist MG624 decrease of the angiogenesis effect of nicotine in vitro and in xenograft mouse model of small cell lung cancer. The effect of MG624 is probably mediated by inhibition of nicotine induced release of fibroblast growth factor 2 (FGF2) through activation of early growth response gene 1 [51]. Another research indicated that knockdown of α7-nAChR suppressed nicotine induced tubulogenesis of human retinal endothelial cells.

Other subunits of nAChRs are also expressed in the endothelia cells [52]. Interestingly, knockdown of CHRNA9 in endothelial cells enhanced nicotine induced cell proliferation, migration, and tube formation [53]. The effect is probably caused by the compensatory increase of α7-nAChR on the cell membrane of endothelial cells.

The angiogenesis effect of nAChRs can function independently of exogenously added nicotine. Matrigel tube formation assay showed that nAChR antagonists have suppressive effects on angiogenesis [50]. Interestingly, antagonists of endothelial nAChR can also suppress the angiogenic processes of VEGF and FGF. These findings suggest pathways involved in nAChRs mediated signaling interact with the angiogenesis pathways of VEGF and FGF. And microarray studies indicated concordant transcriptional profiles induced by nicotine, VEGF, and FGF, which suggest angiogenic growth factors and cholinergic signaling pathways have close interactions [54]. In addition, endothelial cells can synthesize acetylcholine as an autocrine angiogenic factor [55, 56]. Besides acetylcholine, SLURP1/SLURP2 can also function as endogenous agonists of nAChR, and these proteins allosterically modify and activate nAChRs [57].

5. nAChRs Signaling in Lung Cancers

In pulmonary neuroendocrine cells (PNECs), nicotine or NNK stimulates the proliferation of PNECs in vitro through activation of protein kinase C (PKC), the serine/threonine kinase RAF1, the mitogen activated kinases ERK1 and ERK2, and the transcription factors FOS, JUN, and MYC. These responses are abolished by α7-nAChR specific antagonist, indicating that α7-nAChR is the primary mediator of nicotine and NNK signaling [58–60]. Similarly, serotonin and bombesin, the two autocrine growth factors, can activate the same signaling cascade in vitro [58, 59], whereas the effects of nicotine or NNK were abolished by a serotonin uptake inhibitor [59]. Nicotine or NNK induced DNA synthesis is effectively blocked by Ca2+ channel blockers [61]. In addition, NNK can cause ERK1-ERK2 dependent phosphorylation of m-calpains and μ-calpains and further promote the migration of small cell lung cancer (SCLC) cells [62]. The response can be blocked by ERK1-ERK2 specific inhibitors or RNAi silencing of calpains [62]. Furthermore, NNK can activate BCL-2 to inhibit apoptosis of SCLC cells, whereas PKC inhibitor staurosporine, ERK1-ERK2 inhibitor PD98059, or knockdown of MYC can block the effect [63].

The release of autocrine growth factors such as serotonin and mammalian bombesin is an important downstream response of α7-nAChR to stimulate the growth of cancer cells. In addition, several other autocrine growth factors of SCLC cells also activate the RAF1-ERK signaling pathway to cooperate with the α7-nAChR signaling cascade to stimulate the proliferation of cancer cells [64]. Consistently, inhibition of PKC or ERK1-ERK2 or upregulation of intracellular cyclic adenosine monophosphate (cAMP) can strongly suppress the nAChR-stimulated responses of SCLC in vitro [65, 66]. The suppression is probably mediated by inhibition of RAF1 by cAMP-dependent protein kinase A [67].

Heteromeric nAChRs are also expressed in non-small-cell lung cancers (NSCLCs); however, in smokers the nicotine or NNK responses are generally mediated by α7-nAChR as a result of desensitization of heteromeric receptors. Nicotine or NNK treatment of NSCLCs stimulates the proliferation and inhibits chemotherapy-induced apoptosis through activation of PI3K-AKT pathway and nuclear factor-κB (NF-κB) [44, 68]. Consistently, constitutive activation of AKT is observed in NSCLCs to promote resistance of apoptosis in chemotherapy [69]. And nicotine induced AKT-dependent upregulation of survivin and E3 ubiquitin-protein ligase (XIAP) to mediate the antiapoptotic response of NSCLCs [70]. In addition, α7-nAChR also mediates the activation of β-arrestin and protooncogene tyrosine-protein kinase Src (SRC) to promote the proliferation of NSCLC cells [71].

In immortalized human bronchial epithelial cells the downstream signal pathways activated by nAChRs include ERK1-ERK2 activated transcription factors, signal transducer and activator of transcription 1 (STAT1), NF-κB, and GATA-binding factor 3 (GATA3). Interestingly, antagonist of α7-nAChR specifically blocked the stimulating effects of NNK, whereas antagonist of the heteromeric nAChRs specifically blocked the NNN responses [72]. nAChRs also control the release of growth factors such as proepidermal growth factor (EGF) in large airway epithelial cells; the effects are blocked by the selective antagonists of α7-nAChR through intervening with the Ras-Raf-ERK signaling cascade [73]. Thus the EGFR signaling pathway is incorporated into the nAChRs growth stimulatory effects in large airway epithelial cells.

The deregulation of nAChR subunits in primary lung cancer tissues is also evidenced by the epigenetic alterations of the nAChR genes [74–76]. Paliwal et al. reported that cholinergic receptor, nicotinic, alpha 3 (CHRNA3) gene encoding the α3-nAChR subunit is frequently hypermethylated and silenced in lung cancer, and DNA methylation inhibitors can cause demethylation of CHRNA3 promoter and reactivation of the gene [75]. Ectopic expression of α3-nAChR restored the protein level of the α3 receptor in H1975 lung cancer cell line and induced apoptosis [73]. They also observed a dramatic increase of Ca2+ influx response in the presence of nicotine elicited by knockdown of CHRNA3 in α3-nAChR positive lung cancer cells, followed by activation of the AKT prosurvival pathway. Moreover, α3-nAChR depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRNA3 gene in human cancer. Interestingly, they found CHRNA3, but not CHRNA5, is often hypermethylated and downregulated in cancer tissues, whereas a 30-fold upregulation of CHRNA5 expression is observed in lung cancers compared with the normal lung [75]. Consistently, in a separate study α5-nAChR and α3-nAChR are identified as negative regulator of α7-nAChR mediated nicotine responses in human normal and bronchial cancer [21]. Knockdown of CHRNA3 and CHRNA5 in bronchial cancer cells and esophageal cancer cells leads to increased calcium influx induced by nicotine, which could be explained by the compensatory increase of the assembly of functional α7-nAChR on the cell membrane. Importantly, they have also identified downregulation of p63 after knockdown of CHRNA5 or CHRNA3, which offered an explanation for the resistance to apoptosis in CHRNA3 downregulated lung cancers. Moreover, knockdown of CHRNA3 in A549 cells downregulates the cell-cell adhesion molecules and reduces the components of tight junctions (ZO-1) and adherens junctions (P120), analogous to epithelial cells undergoing epithelial-mesenchyme transition [77]. Together these findings suggest that α5-nAChR and α3-nAChR mediate the apoptotic responses and suppress the adhesion and migration of primary lung cancer cells and normal bronchial cells. In addition, the regulatory functions are mediated by the heteromeric (α3β2)2α5-nAChR rather than the AChR5 subunit alone.

6. nAChRs Signaling in Pancreatic Cancer

Cigarette smoking is most frequent risk factor associated with pancreatic cancer [78–81]. NNK can induce pancreatic cancer through the genotoxic effect of DNA adducts causing RAS gene mutations [40] but also has a hyperproliferative effect on pancreatic duct epithelia through β-adrenergic transactivation of EGF receptors [82, 83]. Recently, Al-Wadei et al. reported that nicotine and NNK promote the synthesis and release of adrenaline and noradrenaline to promote the proliferation and migration of pancreatic cancer cells [84]. And RNA knockdown experiments indicate the effect is mediated by α3-, α5-, and α7-nAChRs. Similarly, the process is coupled with increased β-adrenergic cAMP-dependent signaling and release of arachidonic acid in pancreatic cancer cell lines [45, 82, 85]. And the activation of CREB, ERK, SRC, and AKT pathways has been identified to mediate the oncogenic responses of nAChRs. Together these findings suggest nAChR mediated catecholamine synthesis, release, and transactivation of the EGFR signaling pathway promote the progression of pancreatic cancers.

Besides, nicotine/cigarette smoke promotes metastasis of pancreatic cancer through α7-nAChR mediated Mucin-4 (MUC4) upregulation. Chronic exposure to nicotine or cigarette smoke leads to increased expression of MUC4 in pancreatic cancer through activation of the α7-nAChR/JAK2/STAT3 and the MEK/ERK1/ERK2 signaling cascade [86]. And tobacco smoking induces chronic inflammation to trigger the development of pancreatic cancer [87]. The oncogenic effects of nAChR signaling in pancreatic cancer are also supported by the animal experiments, and N-nitroso compounds, formed from nicotine by nitrosation during the processing of tobacco plants, can cause pancreatic cancer in Syrian golden hamsters [88].

7. nAChRs Signaling in Oral and Esophageal Cancers

In oral and esophageal cancer, besides α7-nAChR, heteromeric nAChR composed of α3 and α5 subunits also regulates the responses of nicotine and NNK [15, 89, 90]. And chronic exposure to nicotine or tobacco smoke selectively upregulates α5-nAChR and α7-nAChR subunits in oral keratinocytes [55]. Similar to lung cancer cells [14], NNK preferentially binds to α7-nAChR with higher affinity, whereas NNN binds to heterometric nAChRs with higher affinity in oral and esophageal cancer cells. In esophageal carcinoma nAChRs mediated nitrosamine responses by activating signaling pathways such as Ras-Raf-ERK1-ERK2 and the JAK2-STAT3 pathway and NF-κB and in GATA3 and STAT1 to promote the growth and inhibit apoptosis of the cancer cells [7].

Consistent with the neurotransmitters’ effects on cancer, nAChRs mediated synthesis and release of adrenaline and noradrenaline are important downstream responses of nicotine stimulated growth of esophageal cancers. Consistently, increased proliferation of esophageal cancer cells is observed by adrenaline treatment, which is mediated by activation of Ras-MARK pathway and transactivation of EGFR [91, 92]. The mechanism is similar to the signal transduction mediated by nAChRs in colon cancer and pancreatic cancer [38, 93].

Other nAChRs mediated oncogenic signaling pathways are also implicated in esophageal cancer. Arredondo et al. reported that secreted mammalian SLURP1/SLURP2 are cell endogenous allosteric modulators of nAChRs signaling that enhance the responses of acetylcholine and trigger proapoptotic activity in human keratinocytes [89]. The expression of SLURP1 and SLURP2 is reduced in esophageal cancers, and exogenous expression of SLURP1 and SLURP2 in esophageal cancer cells reduced the colony forming ability of the cells in the presence of nitrosamine, also inhibiting the growth of NNK transformed keratinocytes in mouse xenograft. Recent work done by our group indicated nAChRs also mediated the nicotine activation of the oncogenic YAP1 of the Hippo signaling pathway in esophageal cancer, we also found upregulation of YAP1 in esophageal cancer samples is significantly associated with the smoking history of the patients, and the effects are regulated by PKC signaling, as PKC specific inhibitor can abolish the activation of YAP1 by nicotine treatment [94] (Figures 2(a) and 2(b)). Besides, nicotine promotes head and neck cancer through activation of endogenous FOXM1 activity by loss of heterozygosity involving the whole of chromosome 13 and copy number abnormality (CNA) in oral keratinocytes (KC) [53].

(a)

(b)

8. Conclusion Remarks

An increasing body of evidence suggests that nAChRs stay at the center of regulatory pathways of cholinergic and nicotinic signaling to regulate the growth and migration of the cells, also regulating angiogenesis of the endothelial cells during physiological and pathological conditions. In accord with the findings of multiple GWAS which indicate that SNPs of the gene cluster 15q25, which contains CHRNA3, CHRNA5, CHRNB4, are associated with increased risks of lung cancer and COPD as well as nicotine-dependence, recent cellular and molecular studies on nAChRs indicate that chronic exposure to nicotine or nicotine-derived carcinogenic nitrosamines upregulates the α7-nAChR and α9-nAChR and desensitizes the heteromeric α4β2-nAChR to activate the oncogenic pathways, promotes tumor angiogenesis, and inhibits drug induced apoptosis in multiple types of cancers. Although α7-nAChR is the oncogenic receptor responsible for most of the oncogenic responses in cancer, α9-nAChR has been shown to be upregulated in estrogen receptor positive breast cancer cells, and α9-nAChR stimulates the initiation and progression of breast cancer in coalition with estrogen receptor [95]. Collectively, these recent findings suggest that nAChR mediated oncogenic signaling plays an important role in the initiation and progression of cancer, which functions in parallel with the mutagenic and cytotoxic effects of tobacco smoke to promote the growth and angiogenesis of the tobacco related cancers. Thus nAChRs yield as promising new targets for the prevention, diagnosis, and treatment of tobacco related cancers.

Conflict of Interests

The author declares that there is no conflict of interests regarding the publication of this paper.

References

I. Wessler and C. J. Kirkpatrick, “Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans,” British Journal of Pharmacology, vol. 154, no. 8, pp. 1558–1571, 2008.
View at: Publisher Site | Google Scholar
A. Sobel, M. Weber, and J. P. Changeux, “Large-scale purification of the acetylcholine-receptor protein in its membrane-bound and detergent-extracted forms from Torpedo marmorata electric organ,” European Journal of Biochemistry, vol. 80, no. 1, pp. 215–224, 1977.
View at: Publisher Site | Google Scholar
R. D. O'Brien, M. E. Eldefrawi, and A. T. Eldefrawi, “Isolation of acetylcholine receptors,” Annual Review of Pharmacology, vol. 12, pp. 19–34, 1972.
View at: Publisher Site | Google Scholar
A. Karlin, “The acetylcholine receptor: progress report,” Life Sciences, vol. 14, no. 8, pp. 1385–1415, 1974.
View at: Publisher Site | Google Scholar
J.-L. Galzi, F. Revah, A. Bessis, and J.-P. Changeux, “Functional architecture of the nicotinic acetylcholine receptor: from electric organ to brain,” Annual Review of Pharmacology and Toxicology, vol. 31, no. 1, pp. 37–72, 1991.
View at: Publisher Site | Google Scholar
A. N. Placzek, T. A. Zhang, and J. A. Dani, “Nicotinic mechanisms influencing synaptic plasticity in the hippocampus,” Acta Pharmacologica Sinica, vol. 30, no. 6, pp. 752–760, 2009.
View at: Publisher Site | Google Scholar
H. M. Schuller, “Is cancer triggered by altered signalling of nicotinic acetylcholine receptors?” Nature Reviews Cancer, vol. 9, no. 3, pp. 195–205, 2009.
View at: Publisher Site | Google Scholar
S. S. Hecht, “Tobacco carcinogens, their biomarkers and tobacco-induced cancer,” Nature Reviews Cancer, vol. 3, no. 10, pp. 733–744, 2003.
View at: Publisher Site | Google Scholar
J.-P. Changeux, “Nicotinic receptors and nicotine addiction,” Comptes Rendus Biologies, vol. 332, no. 5, pp. 421–425, 2009.
View at: Publisher Site | Google Scholar
G. S. Portugal and T. J. Gould, “Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: converging evidence from human and animal research,” Behavioural Brain Research, vol. 193, no. 1, pp. 1–16, 2008.
View at: Publisher Site | Google Scholar
J. Lindstrom, R. Anand, V. Gerzanich, X. Peng, F. Wang, and G. Wells, “Structure and function of neuronal nicotinic acetylcholine receptors,” Progress in Brain Research, vol. 109, pp. 125–137, 1996.
View at: Publisher Site | Google Scholar
M. Gopalakrishnan, B. Buisson, E. Touma et al., “Stable expression and pharmacological properties of the human α 7 nicotinic acetylcholine receptor,” European Journal of Pharmacology, vol. 290, no. 3, pp. 237–246, 1995.
View at: Google Scholar
H. Kawai and D. K. Berg, “Nicotinic acetylcholine receptors containing α7 subunits on rat cortical neurons do not undergo long-lasting inactivation even when up-regulated by chronic nicotine exposure,” Journal of Neurochemistry, vol. 78, no. 6, pp. 1367–1378, 2001.
View at: Publisher Site | Google Scholar
H. M. Schuller and M. Orloff, “Tobacco-specific carcinogenic nitrosamines: ligands for nicotinic acetylcholine receptors in human lung cancer cells,” Biochemical Pharmacology, vol. 55, no. 9, pp. 1377–1384, 1998.
View at: Publisher Site | Google Scholar
J. Arredondo, A. I. Chernyavsky, and S. A. Grando, “Nicotinic receptors mediate tumorigenic action of tobacco-derived nitrosamines on immortalized oral epithelial cells,” Cancer Biology and Therapy, vol. 5, no. 5, pp. 511–517, 2006.
View at: Publisher Site | Google Scholar
H. M. Schuller, B. Porter, and A. Riechert, “Beta-adrenergic modulation of NNK-induced lung carcinogenesis in hamsters,” Journal of Cancer Research and Clinical Oncology, vol. 126, no. 11, pp. 624–630, 2000.
View at: Publisher Site | Google Scholar
V. Boswell-Smith and D. Spina, “PDE4 inhibitors as potential therapeutic agents in the treatment of COPD-focus on roflumilast,” International journal of Chronic Obstructive Pulmonary Disease, vol. 2, no. 2, pp. 121–129, 2007.
View at: Google Scholar
N. L. Saccone, R. C. Culverhouse, T.-H. Schwantes-An et al., “Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD,” PLoS Genetics, vol. 6, no. 8, Article ID e1001053, 2010.
View at: Publisher Site | Google Scholar
C. A. Wassenaar, Q. Dong, Q. Wei, C. I. Amos, M. R. Spitz, and R. F. Tyndale, “Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk,” Journal of the National Cancer Institute, vol. 103, no. 17, pp. 1342–1346, 2011.
View at: Publisher Site | Google Scholar
X. Chen, I. P. Gorlov, K. W. Merriman et al., “Association of smoking with tumor size at diagnosis in non-small cell lung cancer,” Lung Cancer, vol. 74, no. 3, pp. 378–383, 2011.
View at: Publisher Site | Google Scholar
A. M. Krais, A. H. Hautefeuille, M.-P. Cros et al., “CHRNA5 as negative regulator of nicotine signaling in normal and cancer bronchial cells: effects on motility, migration and p63 expression,” Carcinogenesis, vol. 32, no. 9, pp. 1388–1395, 2011.
View at: Publisher Site | Google Scholar
F. S. Falvella, A. Galvan, E. Frullanti et al., “Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk,” Clinical Cancer Research, vol. 15, no. 5, pp. 1837–1842, 2009.
View at: Publisher Site | Google Scholar
F. S. Falvella, A. Galvan, F. Colombo, E. Frullanti, U. Pastorino, and T. A. Dragani, “Promoter polymorphisms and transcript levels of nicotinic receptor CHRNA5,” Journal of the National Cancer Institute, vol. 102, no. 17, pp. 1366–1370, 2010.
View at: Publisher Site | Google Scholar
A. Chikova and S. A. Grando, “Naturally occurring variants of human A9 nicotinic receptor differentially affect bronchial cell proliferation and transformation,” PLoS ONE, vol. 6, no. 11, Article ID e27978, 2011.
View at: Publisher Site | Google Scholar
P. Brennan, P. Hainaut, and P. Boffetta, “Genetics of lung-cancer susceptibility,” The Lancet Oncology, vol. 12, no. 4, pp. 399–408, 2011.
View at: Publisher Site | Google Scholar
J.-P. Changeux, “Nicotine addiction and nicotinic receptors: lessons from genetically modified mice,” Nature Reviews Neuroscience, vol. 11, no. 6, pp. 389–401, 2010.
View at: Publisher Site | Google Scholar
C. Wu, Z. Hu, D. Yu et al., “Genetic variants on chromosome 15q25 associated with lung cancer risk in Chinese populations,” Cancer Research, vol. 69, no. 12, pp. 5065–5072, 2009.
View at: Publisher Site | Google Scholar
A. Chédotal, G. Kerjan, and C. Moreau-Fauvarque, “The brain within the tumor: new roles for axon guidance molecules in cancers,” Cell Death and Differentiation, vol. 12, no. 8, pp. 1044–1056, 2005.
View at: Publisher Site | Google Scholar
D. Palm and F. Entschladen, Neoneurogenesis and the Neuro-Neoplastic Synapse. Neuronal Activity in Tumor Tissue, Karger Publishers, Basel, Switzerland, 2007.
F. Entschladen, D. Palm, B. Niggemann, and K. S. Zaenker, “The cancer's nervous tooth: considering the neuronal crosstalk within tumors,” Seminars in Cancer Biology, vol. 18, no. 3, pp. 171–175, 2008.
View at: Publisher Site | Google Scholar
F. Zafra, D. Lindholm, E. Castren, J. Hartikka, and H. Thoenen, “Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes,” Journal of Neuroscience, vol. 12, no. 12, pp. 4793–4799, 1992.
View at: Google Scholar
S. J. French, T. Humby, C. H. Horner, M. V. Sofroniew, and M. Rattray, “Hippocampal neurotrophin and trk receptor mRNA levels are altered by local administration of nicotine, carbachol and pilocarpine,” Molecular Brain Research, vol. 67, no. 1, pp. 124–136, 1999.
View at: Publisher Site | Google Scholar
H. M. Schuller, H. A. N. Al-wadei, M. F. Ullah, and H. K. Plummer III, “Regulation of pancreatic cancer by neuropsychological stress responses: a novel target for intervention,” Carcinogenesis, vol. 33, no. 1, pp. 191–196, 2012.
View at: Publisher Site | Google Scholar
H. M. Schuller, P. K. Tithof, M. Williams, and H. Plummer III, “The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a β-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via β-adrenergic receptor-mediated release of arachidonic acid,” Cancer Research, vol. 59, no. 18, pp. 4510–4515, 1999.
View at: Google Scholar
E. Laag, M. Majidi, M. Cekanova, T. Masi, T. Takahashi, and H. M. Schuller, “NNK activates ERK1/2 and CREB/ATF-1 via β-1-AR and EGFR signaling in human lung adenocarcinoma and small airway epithelial cells,” International Journal of Cancer, vol. 119, no. 7, pp. 1547–1552, 2006.
View at: Publisher Site | Google Scholar
M. Majidi, H. A. Al-Wadei, T. Takahashi, and H. M. Schuller, “Nongenomic β estrogen receptors enhance β1 adrenergic signaling induced by the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human small airway epithelial cells,” Cancer Research, vol. 67, no. 14, pp. 6863–6871, 2007.
View at: Publisher Site | Google Scholar
V. Y. Shin, W. K. K. Wu, Y.-N. Ye et al., “Nicotine promotes gastric tumor growth and neovascularization by activating extracellular signal-regulated kinase and cyclooxygenase-2,” Carcinogenesis, vol. 25, no. 12, pp. 2487–2495, 2004.
View at: Publisher Site | Google Scholar
H. P. S. Wong, L. Yu, E. K. Y. Lam, E. K. K. Tai, W. K. K. Wu, and C.-H. Cho, “Nicotine promotes colon tumor growth and angiogenesis through β-adrenergic activation,” Toxicological Sciences, vol. 97, no. 2, pp. 279–287, 2007.
View at: Publisher Site | Google Scholar
H. P. S. Wong, L. Yu, E. K. Y. Lam, E. K. K. Tai, W. K. K. Wu, and C. H. Cho, “Nicotine promotes cell proliferation via α7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells,” Toxicology and Applied Pharmacology, vol. 221, no. 3, pp. 261–267, 2007.
View at: Publisher Site | Google Scholar
D. H. Phillips, “Smoking-related DNA and protein adducts in human tissues,” Carcinogenesis, vol. 23, no. 12, pp. 1979–2004, 2002.
View at: Publisher Site | Google Scholar
R.-J. Chen, Y.-S. Ho, H.-R. Guo, and Y.-J. Wang, “Rapid activation of Stat3 and ERK1/2 by nicotine modulates cell proliferation in human bladder cancer cells,” Toxicological Sciences, vol. 104, no. 2, pp. 283–293, 2008.
View at: Publisher Site | Google Scholar
H. M. Schuller, H. A. N. Al-Wadei, and M. Majidi, “Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma,” Carcinogenesis, vol. 29, no. 10, pp. 1979–1985, 2008.
View at: Publisher Site | Google Scholar
J. Joseph, B. Niggemann, K. S. Zaenker, and F. Entschladen, “The neurotransmitter γ-aminobutyric acid is an inhibitory regulator for the migration of SW 480 colon carcinoma cells,” Cancer Research, vol. 62, no. 22, pp. 6467–6469, 2002.
View at: Google Scholar
K. A. West, J. Brognard, A. S. Clark et al., “Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells,” The Journal of Clinical Investigation, vol. 111, no. 1, pp. 81–90, 2003.
View at: Publisher Site | Google Scholar
H. M. Schuller, H. A. N. Al-Wadei, and M. Majidi, “GABAB receptor is a novel drug target for pancreatic cancer,” Cancer, vol. 112, no. 4, pp. 767–778, 2008.
View at: Publisher Site | Google Scholar
C. Heeschen, J. J. Jang, M. Weis et al., “Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis,” Nature Medicine, vol. 7, no. 7, pp. 833–839, 2001.
View at: Publisher Site | Google Scholar
B.-Q. Zhu, C. Heeschen, R. E. Sievers et al., “Second hand smoke stimulates tumor angiogenesis and growth,” Cancer Cell, vol. 4, no. 3, pp. 191–196, 2003.
View at: Publisher Site | Google Scholar
C. Heeschen, E. Chang, A. Aicher, and J. P. Cooke, “Endothelial progenitor cells participate in nicotine-mediated angiogenesis,” Journal of the American College of Cardiology, vol. 48, no. 12, pp. 2553–2560, 2006.
View at: Publisher Site | Google Scholar
M. Yu, Q. Liu, J. Sun, K. Yi, L. Wu, and X. Tan, “Nicotine improves the functional activity of late endothelial progenitor cells via nicotinic acetylcholine receptors,” Biochemistry and Cell Biology, vol. 89, no. 4, pp. 405–410, 2011.
View at: Publisher Site | Google Scholar
C. Heeschen, M. Weis, A. Aicher, S. Dimmeler, and J. P. Cooke, “A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors,” Journal of Clinical Investigation, vol. 110, no. 4, pp. 527–536, 2002.
View at: Publisher Site | Google Scholar
K. C. Brown, J. K. Lau, A. M. Dom et al., “MG624, an alpha7-nAChR antagonist, inhibits angiogenesis via the Egr-1/FGF2 pathway,” Angiogenesis, vol. 15, no. 1, pp. 99–114, 2012.
View at: Publisher Site | Google Scholar
J. C. F. Wu, A. Chruscinski, V. A. De Jesus Perez et al., “Cholinergic modulation of angiogenesis: role of the 7 nicotinic acetylcholine receptor,” Journal of Cellular Biochemistry, vol. 108, no. 2, pp. 433–446, 2009.
View at: Publisher Site | Google Scholar
E. Gemenetzidis, A. Bose, A. M. Riaz et al., “FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation,” PLoS ONE, vol. 4, no. 3, Article ID e4849, 2009.
View at: Publisher Site | Google Scholar
M. K. Ng, J. Wu, E. Chang et al., “A central role for nicotinic cholinergic regulation of growth factor-induced endothelial cell migration,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 1, pp. 106–112, 2007.
View at: Google Scholar
J. Arredondo, A. I. Chernyavsky, D. L. Jolkovsky, K. E. Pinkerton, and S. A. Grando, “Receptor-mediated tobacco toxicity: alterations of the NF-κB expression and activity downstream of α7 nicotinic receptor in oral keratinocytes,” Life Sciences, vol. 80, no. 24-25, pp. 2191–2194, 2007.
View at: Publisher Site | Google Scholar
I. Wessler, C. J. Kirkpatrick, and K. Racké, “The cholinergic ‘pitfall’: acetylcholine, a universal cell molecule in biological systems, including humans,” Clinical and Experimental Pharmacology and Physiology, vol. 26, no. 3, pp. 198–205, 1999.
View at: Publisher Site | Google Scholar
Y. Moriwaki, K. Yoshikawa, H. Fukuda, Y. X. Fujii, H. Misawa, and K. Kawashima, “Immune system expression of SLURP-1 and SLURP-2, two endogenous nicotinic acetylcholine receptor ligands,” Life Sciences, vol. 80, no. 24-25, pp. 2365–2368, 2007.
View at: Publisher Site | Google Scholar
M. G. Cattaneo, A. Codignola, L. M. Vicentini, F. Clementi, and E. Sher, “Nicotine stimulates a serotonergic autocrine loop in human small-cell lung carcinoma,” Cancer Research, vol. 53, no. 22, pp. 5566–5568, 1993.
View at: Google Scholar
B. A. Jull, H. Plummer, and H. Schuller, “Nicotinic receptor-mediated activation by the tobacco-specific nitrosamine NNK of a Raf-1/MAP kinase pathway, resulting in phosphorylation of c-myc in human small cell lung carcinoma cells and pulmonary neuroendocrine cells,” Journal of Cancer Research and Clinical Oncology, vol. 127, no. 12, pp. 707–717, 2001.
View at: Google Scholar
A. Codignola, P. Tarroni, M. G. Cattaneo, L. M. Vicentini, F. Clementi, and E. Sher, “Serotonin release and cell proliferation are under the control of α-bungarotoxin-sensitive nicotinic receptors in small-cell lung carcinoma cell lines,” FEBS Letters, vol. 342, no. 3, pp. 286–290, 1994.
View at: Publisher Site | Google Scholar
B. J. Sheppard, M. Williams, H. K. Plummer, and H. M. Schuller, “Activation of voltage-operated Ca²⁺-channels in human small cell lung carcinoma by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone,” International Journal of Oncology, vol. 16, no. 3, pp. 513–518, 2000.
View at: Google Scholar
L. Xu and X. Deng, “Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induces phosphorylation of μ- and m-calpain in association with increased secretion, cell migration, and invasion,” The Journal of Biological Chemistry, vol. 279, no. 51, pp. 53683–53690, 2004.
View at: Publisher Site | Google Scholar
Z. Jin, F. Gao, T. Flagg, and X. Deng, “Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation,” The Journal of Biological Chemistry, vol. 279, no. 38, pp. 40209–40219, 2004.
View at: Publisher Site | Google Scholar
T. Seufferlein and E. Rozengurt, “Galanin, neurotensin, and phorbol esters rapidly stimulate activation of mitogen-activated protein kinase in small cell lung cancer cells,” Cancer Research, vol. 56, no. 24, pp. 5758–5764, 1996.
View at: Google Scholar
H. K. Plummer III, M. S. Dhar, M. Cekanova, and H. M. Schuller, “Expression of G-protein inwardly rectifying potassium channels (GIRKs) in lung cancer cell lines,” BMC Cancer, vol. 5, article 104, 2005.
View at: Publisher Site | Google Scholar
S. H. Shafer, S. H. Phelps, and C. L. Williams, “Reduced DNA synthesis and cell viability in small cell lung carcinoma by treatment with cyclic AMP phosphodiesterase inhibitors,” Biochemical Pharmacology, vol. 56, no. 9, pp. 1229–1236, 1998.
View at: Publisher Site | Google Scholar
J.-P. Pursiheimo, A. Kieksi, M. Jalkanen, and M. Salmivirta, “Protein kinase A balances the growth factor-induced Ras/ERK signaling,” FEBS Letters, vol. 521, no. 1–3, pp. 157–164, 2002.
View at: Publisher Site | Google Scholar
J. Tsurutani, S. S. Castillo, J. Brognard et al., “Tobacco components stimulate Akt-dependent proliferation and NFκB-dependent survival in lung cancer cells,” Carcinogenesis, vol. 26, no. 7, pp. 1182–1195, 2005.
View at: Publisher Site | Google Scholar
J. Brognard, A. S. Clark, Y. Ni, and P. A. Dennis, “Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation,” Cancer Research, vol. 61, no. 10, pp. 3986–3997, 2001.
View at: Google Scholar
P. Dasgupta, R. Kinkade, B. Joshi, C. DeCook, E. Haura, and S. Chellappan, “Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 16, pp. 6332–6337, 2006.
View at: Publisher Site | Google Scholar
P. Dasgupta, S. Rastogi, S. Pillai et al., “Nicotine induces cell proliferation by β-arrestin-mediated activation of Src and Rb-Raf-1 pathways,” Journal of Clinical Investigation, vol. 116, no. 8, pp. 2208–2217, 2006.
View at: Publisher Site | Google Scholar
J. Arredondo, A. I. Chernyavsky, and S. A. Grando, “The nicotinic receptor antagonists abolish pathobiologic effects of tobacco-derived nitrosamines on BEP2D cells,” Journal of Cancer Research and Clinical Oncology, vol. 132, no. 10, pp. 653–663, 2006.
View at: Publisher Site | Google Scholar
E. Martínez-García, M. Irigoyen, E. Ansó, J. J. Martínez-Irujo, and A. Rouzaut, “Recurrent exposure to nicotine differentiates human bronchial epithelial cells via epidermal growth factor receptor activation,” Toxicology and Applied Pharmacology, vol. 228, no. 3, pp. 334–342, 2008.
View at: Publisher Site | Google Scholar
D. C.-L. Lam, L. Girard, R. Ramirez et al., “Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers,” Cancer Research, vol. 67, no. 10, pp. 4638–4647, 2007.
View at: Publisher Site | Google Scholar
A. Paliwal, T. Vaissière, A. Krais et al., “Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer,” Cancer Research, vol. 70, no. 7, pp. 2779–2788, 2010.
View at: Publisher Site | Google Scholar
J. D. Minna, “Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer,” The Journal of Clinical Investigation, vol. 111, no. 1, pp. 31–33, 2003.
View at: Publisher Site | Google Scholar
M. Polette, M. Mestdagt, S. Bindels et al., “β-Catenin and ZO-1: shuttle molecules involved in tumor invasion-associated epithelial-mesenchymal transition processes,” Cells Tissues Organs, vol. 185, no. 1–3, pp. 61–65, 2007.
View at: Publisher Site | Google Scholar
A. V. Patel, C. Rodriguez, L. Bernstein, A. Chao, M. J. Thun, and E. E. Calle, “Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. cohort,” Cancer Epidemiology Biomarkers and Prevention, vol. 14, no. 2, pp. 459–466, 2005.
View at: Publisher Site | Google Scholar
D. Qiu, M. Kurosawa, Y. Lin et al., “Overview of the epidemiology of pancreatic cancer focusing on the JACC Study,” Journal of Epidemiology, vol. 15, supplement 2, pp. S157–S167, 2005.
View at: Publisher Site | Google Scholar
C. S. Fuchs, G. A. Colditz, M. J. Stampfer et al., “A prospective study of cigarette smoking and the risk of pancreatic cancer,” Archives of Internal Medicine, vol. 156, no. 19, pp. 2255–2260, 1996.
View at: Publisher Site | Google Scholar
J. E. Yun, I. Jo, J. Park et al., “Cigarette smoking, elevated fasting serum glucose, and risk of pancreatic cancer in Korean men,” International Journal of Cancer, vol. 119, no. 1, pp. 208–212, 2006.
View at: Publisher Site | Google Scholar
M. D. F. Askari, M.-S. Tsao, and H. M. Schuller, “The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through β-adrenergic transactivation of EGF receptors,” Journal of Cancer Research and Clinical Oncology, vol. 131, no. 10, pp. 639–648, 2005.
View at: Publisher Site | Google Scholar
H. M. Schuller, “Mechanisms of smoking-related lung and pancreatic adenocarcinoma development,” Nature Reviews Cancer, vol. 2, no. 6, pp. 455–463, 2002.
View at: Publisher Site | Google Scholar
M. H. Al-Wadei, H. A. N. Al-Wadei, and H. M. Schuller, “Effects of chronic nicotine on the autocrine regulation of pancreatic cancer cells and pancreatic duct epithelial cells by stimulatory and inhibitory neurotransmitters,” Carcinogenesis, vol. 33, no. 9, pp. 1745–1753, 2012.
View at: Publisher Site | Google Scholar
D. L. Weddle, P. Tithoff, M. Williams, and H. M. Schuller, “β-Adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas,” Carcinogenesis, vol. 22, no. 3, pp. 473–479, 2001.
View at: Publisher Site | Google Scholar
N. Momi, M. P. Ponnusamy, S. Kaur et al., “Nicotine/cigarette smoke promotes metastasis of pancreatic cancer through α7nAChR-mediated MUC4 upregulation,” Oncogene, vol. 32, no. 11, pp. 1384–1395, 2013.
View at: Publisher Site | Google Scholar
U. A. Wittel, K. K. Pandey, M. Andrianifahanana et al., “Chronic pancreatic inflammation induced by environmental tobacco smoke inhalation in rats,” The American Journal of Gastroenterology, vol. 101, no. 1, pp. 148–159, 2006.
View at: Publisher Site | Google Scholar
P. M. Pour, S. Z. Salmasi, and R. G. Runge, “Selective induction of pancreatic ductular tumors by single doses of N-nitrosobis(2-oxopropyl)amine in syrian golden hamsters,” Cancer Letters, vol. 4, pp. 317–323, 1978.
View at: Publisher Site | Google Scholar
J. Arredondo, A. I. Chernyavsky, and S. A. Grando, “SLURP-1 and -2 in normal, immortalized and malignant oral keratinocytes,” Life Sciences, vol. 80, no. 24-25, pp. 2243–2247, 2007.
View at: Publisher Site | Google Scholar
J. Arredondo, A. I. Chernyavsky, D. L. Jolkovsky, K. E. Pinkerton, and S. A. Grando, “Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of α7 nicotinic receptor in oral keratinocytes,” The FASEB Journal, vol. 20, no. 12, pp. 2093–2101, 2006.
View at: Publisher Site | Google Scholar
X. Liu, W. K. K. Wu, L. Yu et al., “Epidermal growth factor-induced esophageal cancer cell proliferation requires transactivation of β-adrenoceptors,” Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 1, pp. 69–75, 2008.
View at: Publisher Site | Google Scholar
X. Liu, W. K. K. Wu, L. Yu et al., “Epinephrine stimulates esophageal squamous-cell carcinoma cell proliferation via β-adrenoceptor-dependent transactivation of extracellular signal-regulated kinase/cyclooxygenase-2 pathway,” Journal of Cellular Biochemistry, vol. 105, no. 1, pp. 53–60, 2008.
View at: Publisher Site | Google Scholar
M. H. Al-Wadei, H. A. N. Al-Wadei, and H. M. Schuller, “Pancreatic cancer cells and normal pancreatic duct epithelial cells express an autocrine catecholamine loop that is activated by nicotinic acetylcholine receptors α3, α5, and α7,” Molecular Cancer Research, vol. 10, no. 2, pp. 239–249, 2012.
View at: Publisher Site | Google Scholar
Y. Zhao, W. Zhou, L. Xue, W. Zhang, and Q. Zhan, “Nicotine activates YAP1 through nAChRs mediated signaling in esophageal squamous cell cancer (ESCC),” PLoS ONE, vol. 9, no. 3, Article ID e90836, 2014.
View at: Publisher Site | Google Scholar
W. O. Lee and S. M. Wright, “Production of endothelin by cultured human endothelial cells following exposure to nicotine or caffeine,” Metabolism: Clinical and Experimental, vol. 48, no. 7, pp. 845–848, 1999.
View at: Publisher Site | Google Scholar
H. Takeuchi, S. Kubota, E. Murakashi et al., “Nicotine-induced CCN2: from smoking to periodontal fibrosis,” Journal of Dental Research, vol. 89, no. 1, pp. 34–39, 2009.
View at: Publisher Site | Google Scholar
K. Yamada, T. Yaguchi, T. Kanno, T. Mukasa, and T. Nishizaki, “Auto-positive feedback regulation for nicotinic acetylcholine receptors by protein kinase C activation,” Cellular Physiology and Biochemistry, vol. 26, no. 2, pp. 247–252, 2010.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2016 Yue Zhao. 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.

PDF Download Citation

Download other formats

Order printed copies

Views

3908

Downloads

1621

Citations