- About this Journal ·
- Abstracting and Indexing ·
- Aims and Scope ·
- Article Processing Charges ·
- Articles in Press ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
Volume 2008 (2008), Article ID 314974, 17 pages
A Role for the PPAR in Cancer Therapy
1Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
2Department of Biosciences, University of Kuopio, 70211 Kuopio, Finland
3Life Sciences Research Unit, University of Luxembourg, 1511 Luxembourg, Luxembourg
4Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles School of Medicine, University of California, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
Received 13 February 2008; Accepted 17 March 2008
Academic Editor: Dipak Panigrahy
Copyright © 2008 Moray J. Campbell 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.
In 1997, the first published reports highlighted PPAR as a novel cancer therapeutic target regulating differentiation of cancer cells. A subsequent flurry of papers described these activities more widely and fuelled further enthusiasm for differentiation therapy, as the ligands for the PPAR were seen as well tolerated and in several cases well-established in other therapeutic contexts. This initial enthusiasm and promise was somewhat tempered by contradictory findings in several murine cancer models and equivocal trial findings. As more understanding has emerged in recent years, a renaissance has occurred in targeting PPAR within the context of either chemoprevention or chemotherapy. This clarity has arisen in part through a clearer understanding of PPAR biology, how the receptor interacts with other proteins and signaling events, and the mechanisms that modulate its transcriptional actions. Equally greater translational understanding of this target has arisen from a clearer understanding of in vivo murine cancer models. Clinical exploitation will most likely require precise and quantifiable description of PPAR actions, and resolution of which targets are the most beneficial to target combined with an understanding of the mechanisms that limits its anticancer effectiveness.
1. Current Understanding of PPARγ Biology
1.1. PPARγ is a Transcription Factor
The human PPARγ was cloned in 1994 and subsequently two murine isoforms were identified in mouse: gamma-1 and gamma-2, resulting from the use of different initiator methionines [1, 2]. Subsequently, at least three isoforms have been identified in humans with common expression in adipocytes and the large intestine and more restricted isoform expression in other tissues . PPARγ plays a key role in energy metabolism and differentiation (reviewed in [4–7]); and reflecting this, the murine PPARγ−/− is embryonically lethal, and if rescued, the animal lacks normal adipocytes .
PPARγ is a phylogenetic member of subfamily 1 the nuclear receptor (NR) superfamily and shares a number of generic mechanistic features in common with other subgroup members, including the retinoic acid receptors (RARs), vitamin D receptor (VDR), farnesoid X receptor (FXR), and liver X receptors (LXRs). These receptors are most commonly located in the nucleus and heterodimerize with one of three retinoid X receptor (RXR) subtypes, to bind specific response elements in target gene regulatory regions. Crystallization studies of PPARγ bound with RXRα proved pivotal for deciphering the basis for heterodimerization with RXR for multiple NRs . The presence of ligand changes the receptor confirmation and also influences choice of association with either coactivator (CoA) or corepressor (CoR) complexes. In the absence of ligand, NR heterodimers are contained within multimeric complexes (2.0 MDa) containing CoRs (e.g., NCOR1) . Also, within these complexes is a range of enzymes, which act to modify the posttranslational status of histone tails and maintain a locally closed repressive chromatin environment, for example, histone deacetylases (HDAC), such as HDAC3 and SIRT1 [10–15].
Ligand activation shifts receptor conformation and distribution to enhance interaction with CoA complexes. A large number of interacting CoA proteins have been described, which can be divided into multiple families including the NCOA/SRC family and members of the large bridging mediator complex including PPARγ binding protein (PBP/MED1) complex [16, 17]. Through the latter, the NR receptor complex links to the cointegrators CBP/p300 and basal transcriptional machinery. For example, PPARγ is known to associate with proteins, such as SRC-1, PGC1-α, CARM1, and a battery of histone modifying enzymes, such as histone acetyltransferases (HAT), which together initiate and promote transactivation [18–22].
The complex choreography of these events is a very active area of research, being at a crossroads of several important areas in contemporary biology, such as multimeric protein complex assembly and chromatin remodeling. Transcription involves cyclical rounds of promoter-specific complex assembly, gene transactivation, complex disassembly, and proteosome-mediated receptor degradation [23–25].
1.2. Newly Characterized and Unique Features of PPARγ
Outside of these general characteristics, uncertainty and ambiguity remain in constructing a predicative schema for understanding PPARγ function and signaling in cancer biology. Some of the uncertainties arise due to a number of structural and regulatory variations of PPARγ outside the core features of NRs, thereby leading to apparently pleiotropic actions. Compounding these difficulties is the issue of studying PPARγ signaling in cancer biology, which is intrinsically an unstable and evolving disease environment.
By contrast to a high-affinity receptor, such as estrogen receptor α (ERα), the members of the subfamily 1 of the NR superfamily are typified by their large ligand-binding domain and may therefore accept different ligands. The PPARγ ligand-binding pocket has a volume of more than 1400 Å3 and therefore can bind a wide range of different lipophilic molecules (see Figure 1). As shown in Figure 1, free fatty acids are metabolized to arachidonic acid, and then through either lipooxygenase (LO) or cyclooxygenase (COX) activities to give rise to a range of natural ligands for PPARγ. Many of these reactions are tightly controlled such that a ligand metabolite is enzymatically generated and cleared.
Circulating and cellular fatty acids give rise to the majority of the natural ligands for PPARγ; therefore, the PPARs in general and PPARγ specifically form a sensing mechanism to maintain homeostasis in changing physiological circumstances such as feeding and exercise. This capacity, as discussed later, is implicated in a range of disease settings including cancer. The omega 6 fatty acid, linoleic acid, is highly inflammatory and therefore carefully controlled in vivo. It is a PPARγ ligand and, through subsequent desaturase and elongase activities, is metabolized to arachidonic acid. A wide range of natural ligands for PPARγ is subsequently derived through arachidonic acid metabolism. LO activity (e.g., arachidonate 5-LO and 15-LO) generates oxidized lipids which act as PPARγ ligands, such as 8 (S)-hydroxyeicosatetraenoic acid (8-(S)-HETE), 15-(S)-HETE, 9-hydroxy-10,12-octadecadienoicacid (9HODE), and 13-HODE. Subsequent dehydrogenase activity, for example, of 13-HODE by 13-HODE dehydrogenase, can result in a further series of PPARγ ligands prior to their subsequent conversion to leuktrienes [26–28].
In parallel, arachidonic acid can be metabolized through cyclooxygenase activity (through COX-1 and -2) to prostaglandins such as PG and subsequently PG, PG, PG, and PG. These compounds exert a diverse range of cellular actions, but key metabolites in these cascades appear to exert potent PPARγ activation. PG, the product of prostaglandin D synthase (encoded by PGDS), is able to undergo nonenzymatic degradation to a J series prostaglandin, 15-deoxy-12,14-prostaglandin (15d-PG), which is a potent PPARγ ligand [26, 29–33]. Similarly, metabolites of PG can activate PPARγ, and their generation is controlled during differentiation, for example, of adipocytes . Many of these reactions appear to be regulated through classical feedback loops, thus, the regulation of arachidonic acid metabolism to provide prostaglandins and leukotrienes is regulated at multiples levels by the actions of PPARγ, for example, regulation of LOs and of COX-2 activity and several of the downstream enzymes [26, 29–35].
The discovery of synthetic ligands for this receptor has been driven by the identification of a number of significant disease settings, in which PPARγ signaling is implicated (inflammation, metabolic disorders, and cancer). A goal of this research is the identification of novel pharmacological compound that display gene- and cell-selective actions . The diversity of cell function, and presumably the relatively large ligand-binding pocket, has encouraged investigators to undertake rational screening approaches to identify a diverse panel of ligands [31, 37–51]. Indeed, novel selective compounds frequently display differential ligand-binding pocket docking sites. Implicit, within these discoveries is that the subtly different induced receptor conformations allow for the different spatiotemporal associations of CoA and ancillary proteins thereby deriving target gene specificity [40, 41, 52–55]. Thiazolidinediones (TZDs) were the first synthetic compounds investigated as PPARγ ligands ; this class also includes rosiglitazone, pioglitazone, and troglitazone. The latter caused a severe idiosyncratic liver problem and thus has been discontinued. The TZDs have proven to be a breakthrough in the therapy of type II diabetes because they decrease insulin resistance by promoting glucose uptake, mitochondrial biogenesis and fatty acid absorption by increasingly differentiated adipocytes (reviewed in ).
This focus at the level of the PPARγ ligand may be too exclusive. For example, the RXR member of this complex can also bind simultaneously with its ligand, which can result in enhanced transcriptional activity (6). Perhaps more importantly, the receptor structure allows it to influence both the basal and regulated transcription levels of target genes independent of ligand. That is, the unliganded structure of PPARγ also exposes a number of critical amino acids on helix 12 that allows CoA binding and may explain the high basal expression levels of PPARγ target genes in the absence of ligand. In this regard, PPARγ most closely resembles another xenobiotic metabolizing NR, constitutive androstane receptor (CAR) . These findings may also suggest that the expression of CoA and CoR proteins are actually more important for regulating gene targets than either the levels or specificity of ligands.
The biology of PPARγ is intimately associated with that of the PGC-1α CoA and a number of other cofactors. The actions of these proteins have most clearly been described in well-established PPARγ systems, such as adipocyte differentiation and regulation of energy metabolism. The Pgc-1α murine knockout displays abnormal metabolic rates, temperature fluctuations, and a lethal cardiac defect [59, 60]. Reflecting its importance for regulating PPARγ function, levels of PGC-1α are tightly regulated by ubiquitination .
PPARγ receptor activity is also regulated by a cohort of posttranslational mechanisms, such as small ubiquitin-related modifier (SUMO) process. Sumoylation of the ligand-binding domain, in the presence of ligand, prevents the release and subsequent ubiquitination of NCOR1, and therefore sustains the repressive action, leading to the so-called ligand-dependent transrepression [62, 63]. This process is antagonized, by the removal of the SUMO modification by the SUSP-1 enzyme  thus establishing a dynamic level of regulation to modify the actual impact of ligand. Furthermore, PPARγ is serine phosphorylated, for example, in response to MAPK signaling leading to nuclear export and attenuation of transcriptional ability [65–67]. By contrast, PBP/MED1 is regulated at multiple sites by phosphorylation to enhance signaling by PPARγ .
To place the expression and regulation of PPARγ within the broader context of NR biology, several scientists have proposed and utilized system level approaches to dissect NR function including PPARγ. One of the most significant examples of this approach has been the spatiotemporal profiling of all 49 murine NRs in multiple tissues at different time points during the circadian rhythm [69, 70]. These approaches have revealed a number of provocative findings. In terms of tissue expression, PPARγ most closely follows Lxrα and Gr, and forms a triumvirate that is intimately implicated in the control of inflammation. The expression of PPARγ was shown also to follow circadian rhythm expression in white adipose tissue and the liver, but not other tissues [69, 70]. Similarly, others have shown that Pgc-1α follows a circadian rhythm in the liver and skeletal muscle of mice , and it cooperates with other NRs to regulate additional members of the clock family.
1.3. Transcriptional Targets of PPARγ
One approach to defining PPARγ specificity has been to describe the cohort of target genes regulated by its actions; generally, these studies involve microarray studies in a range of cell types including adipocytes  and macrophages . Commonly, a range of gene targets has been identified associated with metabolism and transport of lipids, including lipoprotein lipase, fatty acid binding, and transport proteins and acyl-CoA synthase. Similar approaches have been used to study the impact of PPARγ signaling on proliferation and differentiation. For example, in chondorosarcoma and ovarian cancer cells, PPARγ actions were associated with changes in the ratio of BAX to BCL-2, induction of programmed cell death , and upregulation of cyclin-dependent kinase inhibitors (CDKIs), such as CDKN1A (encodes p21(waf1/cip1)) . In MCF-7 breast cancer cells PPARγ upregulated a similar spectrum of CDKIs . A number of studies have identified the IGF axis as a target of PPARγ signaling. For example, in bone marrow cells , and in silico and in vitro studies have characterized a range of PPAR response elements (PPREs) in several insulin-like growth factor binding protein (IGFBPs) genes . Other scientists have attempted to increase the accuracy of gene target identification by using selective ligands, for example, in colorectal cells, and identified gene targets associated with mitotic restraint and cell adhesion [78–82]. Complimentary approaches have utilized adenoviral transfection of receptor subtypes to identify differentially expressed genes, confirmed with chromatin immunoprecipitation (ChIP) approaches .
The accurate prediction of target genes is compounded by the highly integrated nature of PPARγ signaling with other NR family members. For example, its activities are mutually antagonized with ERα signaling, and appear to be cooperative with both VDR and RAR, in part by increased retinol synthesis [84–86]. To investigate this apparent transcriptome plasticity will require the integrations of in silico response element identification protocols combined with ChIP-sequencing approaches to establish specificity and redundancy; comparable approaches have been undertaken for ERα . Building towards this goal, we have undertaken a meta-analyses of PPRE sequences to generate an algorithm to predict PPAR subtype binding and screened chromosome 19, as a test set, to identify and confirm a number of novel genes .
Together, these findings suggest that ligand is just one of a number of mechanisms to regulate receptor function. Other regulatory contributions are determined by PPARγ expression level, isoform, posttranslational modification, location, crosstalk with functionally related receptors and cofactor expression. Together, these components combine with wider transcriptional programs, such as energy utilization, circadian rhythm, and the control of inflammation to drive and specify the timing of transcriptional outputs.
2. Control of Self-Renewing Tissues
2.1. Common Cancers and Leukemia Arise in Self-Renewing Tissues
The weighted contribution of the underlying forces, acting at the levels of genes, chromosomes, signaling cascades and tissue organization, that drive cancer initiation and progression remain poorly understood. Historically, a paradigm of exclusive genetic causality was the basis for investigating cancer etiology and it identified certain key nodal points of cellular control, such as p53. In the postgenomic era, other strong penetrance genes have not been readily identified. The sporadic, multistage acquisition of a cancer phenotype requires disruption of multiple mechanisms of cellular restraint and tissue organization (reviewed in ). Reflecting a sporadic multifactorial cancer phenotype, the single greatest risk factor for most cancers is age, with the average age of onset of breast, prostate, and colon cancer in the sixth and seventh decades of life.
Further understanding of transformation processes has arisen through appreciation of the diverse cell types present at the sites of high-profile malignances. Epithelial linings of the prostate and mammary glands, the gastrointestinal tract and hematological systems all typify self-renewing tissues containing stem cell populations [90–94]. These cells give rise to committed progenitors, and in turn the multiple-cell lineages required for tissue function. Stem cells are relatively rare and long-lived, but frequently quiescent. They are uniquely able to undergo asymmetric division, to give rise to both other stem cells and transiently amplifying populations of progenitor cells, that in turn give rise to the differentiated cell types. The differentiated epithelial cells are functional but short-lived and lost through programmed cell death processes, to be replaced by newly differentiated transiently amplifying cells. Cellular control of the intricate balance of the processes of division, differentiation, and programmed cell death include common roles for Wnt, Hedgehog, and other developmental signal transduction processes. Convergent targets for these signals include key regulators of cellular proliferation, such as Myc and p21(waf1/cip1).
As a result of their long life cycle and high proliferative capacity, stem cells, rather than their short-lived terminally differentiated daughter cells, are the candidates for transformation. However, a range of mechanisms is in place to maintain stem cell genomic integrity, perhaps including retention of the so-called “immortal” DNA strand and enhanced protection mechanisms [95–103]. These controls notwithstanding, the transformation of stem cells has given rise to the concept of cancer stem cells. Such cancer stem cells are well established in leukemia and accumulating evidence supports the presence of these cells in prostate, breast, and colon cancers [104–108].
2.2. Restoration of Controlled Self-Renewal as a Therapeutic Goal
Members of the NR superfamily play a number of well-established roles in the control of self-renewal and the process of normal differentiation. For example, the AR and ERα receptors play pivotal roles in prostate and breast tissue development and maintenance. Distortion of some of these actions is, in turn, central to the development of cancer in these tissues and is targeted therapeutically though antagonism, either completely in the case of the AR, or selectively in the case of the ERα. Agonism of other receptors has been pursued to induce differentiation and inhibit proliferation of cancer cells. The best example of this paradigm is the induction of remission of patients with acute promyelocytic leukemia using the RAR ligand, all-trans retinoic acid, and also to prevent recurrence of head and neck cancers.
As a consequence of the induced terminal differentiation of normal preadipocytes by ligands for PPARγ [1, 2], investigators were encouraged to use TZDs to attempt to induce differentiation of human liposarcoma cells in vivo . Successes in vitro encouraged these same physician-scientists to give troglitazone to a series of patients with liposarcoma, which resulted in a retardation of growth and induction of differentiation of these tumor cells. The long-term effect of TZD on liposarcomas requires further study; nevertheless, these pioneer studies spurred the examination of the effect of TZDs on a number of cancers both in vitro and in vivo in colon, breast, prostate, myeloid leukemia, neuroblastoma, glioblastoma, lymphoma, lung, cervical, bladder, head and neck, esophageal, gastric, pancreatic, and choriocarcinoma cancers [21, 81, 110–140]. The multiple findings from studies illustrate the promise and failings of targeted therapies toward PPARγ to restore mitotic restraint and induce differentiation.
3. PPARγ Signaling in Cancer
3.1. Colon Cancer
To establish a role for PPARγ to protect against the development of colon cancer, investigators have used a range of in vivo and in vitro approaches. In murine models, the expression of PPARγ has been manipulated in either an environmental or a genetic background that displays enhanced susceptibility to colonic cancer. For example, mice with heterozygous germ-line deletions of PPARγ have an increased proclivity to develop N-methyl-N-nitrosourea carcinogen-induced colon cancer compared with wild-type mice, supporting a growth inhibitory role for PPARγ. Significantly, troglitazone reduced the tumor incidence in wild-type but not heterozygote mice . By contrast, other scientists have utilized the well-established AP model of colon cancer with apparently contradictory findings. These mice have a germ-line mutation of the APC gene resulting in deregulated β-catenin signaling, and a very significantly increased frequency of small and large intestinal adenocarcinomas. Surprisingly, administration of TZD to AP mice resulted in increased frequency of colon cancers compared to control animals . Subsequently, however, generation of the intestinal specific PPARγ−/− and AP bigenic mouse demonstrated an unequivocal effect of PPARγ to suppress tumor formation and suggests that significant off-target effects of TZD occur in mice, especially in the AP mouse colon cancer model . Off-target effects of TZD generally appear to also have broad anticancer properties; therefore, the findings in this model appear quite unusual. For example, PPARγ inactive analogs of TZD initiate the proteosomic degradation of β-catenin  and cyclin D1, as well as, interfering with BAX family member interactions to bring about apoptosis [144, 145]. Nevertheless, why AP mice receiving a TZD have more colon cancers still is not fully elucidated. AP mice have high levels of PPARγ in the colonic cells and are inappropriately sequestrated by β-catenin to a unique set of gene targets . Interestingly, PPARα ligands inhibit polyp formation in the AP model  re-enforcing the concept that the TZD-driven enhanced tumor formation in the AP mouse is a model artifact, or at least not general phenomena.
In humans, multiple lines of evidence support an unequivocal function for PPARγ signaling in colon cancer. Mutations of the receptor have been reported, although rare , and polymorphisms are functionally linked with an increased incidence of this cancer . A range of natural and synthetic PPARγ ligands inhibit proliferation, induce programmed cell death and exert prodifferentiation actions in vitro and in vivo, for example, when tested in human xenografts [149–151]. The potency of the ligand actions can be significantly enhanced further by combining the treatment with RXR ligands [124, 152]. Furthermore, this signaling capacity is integrated with the control of other proliferative signals, such as gastrin  (reviewed by ).
3.2. Breast Cancer
The findings on breast cancer support the broad anticancer activities of PPARγ signaling, and also reflect the studies in colon cancer. That is, generally in vitro and in vivo studies support a clear role for this receptor to suppress proliferation, induce differentiation and programmed cell death. In rodent models, the PPARγ agonists block N-nitroso-N-methylurea-induced breast cancer in Sprague-Dawley rats  and DMBA-induced breast cancer in mice . Similarly, PPARγ+/− mice have a greater susceptibility to develop breast and ovarian cancers after their exposure to 7,12-dimethylbenz(a)anthracene .
By contrast, transgenic mice having a constitutively active PPARγ in their breast tissue crossed with the MMTV-neu mouse model of breast cancer displayed accelerated kinetics of breast cancer development, although the authors noted that the tumors surprisingly were more secretory and differentiated in nature . Similar to the AP model, this tumor model depends on deregulated Wnt activity, and the authors suggested that the effects may also reflect aberrant interplay between PPARγ and Wnt signaling.
Human breast cancer cells express PPARγ  and can be targeted, for example, with TZD, and a range of other PPARγ ligands to induce differentiation and inhibition of cell growth both in vitro and in xenograft models, effects which can be enhanced by cotreatment with either retinoids, TGFβ or TNFα [110, 111, 113, 114, 130, 158–163]. For example, PPARγ ligands plus selective retinoid ligands converge on targets, such as RARβ, which is known to act as a tumor suppressor and is commonly silenced in malignancy . Similarly, PPARγ activation results in upregulation of E-cadherin and thereby redistribution of β-catenin . Natural ligands, such as dietary fatty acids, change expression in syndecan-1 with an impact on cytoskeleton structure and the induction of apoptosis . Furthermore, 15d-PG inhibits ERα signaling in a PPARγ-independent manner by covalent modification of the receptor . PPARγ expression is a favorable prognostic factor  and associates with ERα positive disease . A note of caution, however, phase II trials of TZDs in women with hormone refractory metastatic breast cancer were equivocal .
3.3. Prostate Cancer
The biology of the prostate is intimately associated with the synthesis of prostaglandins, as suggested by the name. These growth regulatory factors are readily secreted by the gland  and give rise to the H and D series prostaglandins and 15d-PG. Equally, the biology of the prostate is associated with the metabolism of fatty acids 15S-HETE . Therefore, the prostate seems a tissue where PPARγ may play a strong role in governing cell growth and differentiation. For example, signals derived from PGDS activity in the adjacent stroma, such as PG, activate PPARγ, and control epithelial proliferation .
PPARγ actions in prostate cancer cell lines  and primary cancer models  are well documented and include the induction of type II programmed cell death also known as autophagy . These studies encouraged several groups to undertake clinical trials with PPARγ ligands and disease stabilization was reported . Again in this disease setting, PPARγ-independent actions of TZDs were apparently identified, which were nonetheless potent anticancer signals [172, 173].
Set against these findings, the Evans team used a prostate cancer, the TRAMP model, to demonstrate that PPARγ heterozygote mice have no change in disease progression compared to wild-type litter mates .
3.4. Leukemia and Lymphoma
Previously, we showed that human myeloid and lymphoid leukemia cells express PPARα and PPARγ; ligands, such as troglitazone, inhibited their cell growth [139, 175]. This antiproliferative effect was markedly enhanced in the presence of various retinoids. Also, macrophages and myelomonocytic leukemic cells express abundant PPARγ (73), and PPARγ ligands can induce acute myelomonocytic leukemic cells (THP-1) to differentiate toward macrophages with an increased expression of the CD36 scavenger receptors, as well as other surface markers associated with differentiation including CD11b, CD14, and CD18 (73). Studies by others and us have also shown that PPARγ ligands can inhibit growth and/or induce apoptosis of Hodgkin’s disease  and multiple myeloma cells [176, 177]. The mechanism, by which PPARγ ligand inhibits the proliferation of malignant hematopoietic cells, is not totally clear. Some of the antileukemic effects of PPARγ may be independent of the PPARγ receptor. Furthermore, we have found that a dual PPARα/γ ligand (TZD18) has the ability to induce marked apoptosis and to inhibit growth of lymphoid leukemia cells . In general, the effect of PPARγ ligands on myeloid leukemic growth and differentiation is modest (74).
3.5. Mechanisms of Resistance
Genetically, the PPARγ generally appears to retain its integrity. Rare mutations have been reported and more recently dominant negative variants of the receptor were identified although the biological impact remains to be established firmly . Similarly, altered isoforms may be overexpressed in cancer [180–183]. Cytogenetic rearrangement has been identified in follicular thyroid cancer fusing the PAX-8 transcription factor to PPARγ. In vitro studies suggest PAX-8-PPARγ acts in a dominant negative fashion toward wild-type PPARγ  (Figure 2).
In parallel to these genetic changes, the actions of PPARγ appear to be attenuated by changes in receptor expression and known cofactors. The range of interactions with partner proteins of PPARγ appears to be altered. Interactions with PGC1-α are reduced in several cancers [21, 185, 186]; and oppositely the known CoRs associated with PPARγ are overexpressed and the transcriptional actions of PPARγ are repressed by epigenetic mechanisms involving HDAC3 [187–189]. Equally, the control of posttranslational modifications appears to be altered. SUSP-1 , which removes the SUMO mark (required for ligand-dependent transrepression) appears to be downregulated in a number of breast and prostate cancers . Within the NR network, PPARγ is coexpressed and interacts both positively and negatively with a cohort of other receptors. For example, the ERα and Cyclin D1, (itself a well-known ERα target gene and CoA) can both repress the PPARγ gene promoter [191, 192].
The natural ligands for PPARγ are diverse and it is more challenging to make definitive statements concerning their altered generation in malignancy. Equally, the ability for PPARγ to act in a significant and ligand-independent manner also reduces, to an extent, the significance of ligand levels. These considerations aside, the patterns of ligand generation for PPARγ appear to be altered in malignancy. The balance between LO and COX-2 is dysregualted to favor generation of PGH production  and accompanied by downregulation of PPARγ . This causes an elevation of PG, which in turn is converted to protumorigenic prostaglandins, such as PG, through other synthases. The levels of PG, which gives rise to 15-PG, are closely regulated by an aldo-ketoredcutase (AKR1C3) that is upregulated in malignancy [195–199].
An emergent area of distortion is the extent to which PPARγ signaling is at the mercy of more dominant signal transduction and transcriptional programs. The two tumor promotion models associated with signaling by PPARγ involved elevated levels of signaling by the Wnt pathway. These findings combined with observations on the diversity of genes regulated by the receptor suggest that PPARγ signaling displays plasticity in terms of exact promoter choice. Gene regulatory options are distilled by the combination of receptor-associating cofactors and other signal transduction events. For example, overwhelming Wnt signaling pulls PPARγ to β-catenin gene targets . This plasticity of signaling is probably reflected by the fact that complete loss or mutation of PPARγ in malignancy is relatively rare. Rather, expression is retained but probably sequestrated and distorted by more dominant signaling events. Resolving these interactions will require a quantitative and hierarchical understanding of the signaling paths through which PPARγ combines with other NRs and signal transduction events to regulate cell fates.
4. Is PPARγ a Ligand-Activated Tumor Suppressor?
A tumor suppressor can be characterized as a protein that reduces the probability that a cell in a metazoan will undergo transformation. Initiation and progression of cancer are associated with attenuation, corruption, expression, and protein function of tumor suppressor genes, increasing the likelihood of tumor formation.
Approximately 10 years have past since the first few reports of PPARγ exerting anticancer cellular effects [109, 111]. Taken together the overwhelming body of data suggests that PPARγ can behave as a ligand-activated tumor suppressor.(1)PPARγ ligands through activating PPARγ can inhibit proliferation and induce differentiation and apoptosis of a wide range of neoplastic cell types in vitro and in murine xenograft tumor models.(2)PPARγ−/− mice are more susceptible than wild-type mice to mammary, colon, ovarian, and skin tumors after exposure to carcinogens and enhance tumor formation in some genetic models of cancer, for example, AP model of colon cancer.(3)The actions of these receptors are attenuated in malignancy by genetic, cytogenetic, and epigenetic mechanisms, and ligand generation is compromised. Set against, these data are two findings of enhanced tumor formation related to PPARγ in murine cancer models. TZD enhances tumor formation in the AP model  and the bigenic mice overexpressing PPARγ in the MMTV-neu breast cancer model have more, highly differentiated tumors . In retrospect, these high-profile studies perhaps reveal important facts of the dominant relationship between Wnt signaling over PPARγ in the mouse. This understanding may have important implications for the necessary molecular diagnostics required to target PPARγ therapies most effectively.
5. Future Directions
5.1. Exploiting Dietary Understanding from Chemoprevention
Recently, the appreciation of the impact of diet on either the initiation or progression of cancer has come significantly to the fore. The World Health Organization has now stated that after smoking diet forms the most preventable cause of cancer. Aspects of these relationships are found in breast, prostate, and colon cancer, where the rate of initiation and progression of disease may be influenced both positively and negatively by the cumulative impact of dietary factors over an individual’s lifetime. Beyond the specific micro and macronutrient constituents, the energetic status of an individual is emerging as a risk factor with increased calorific intake and decreased energy expenditure, both contributing deleteriously to cancer initiation and progression (reviewed in ).
The NR network has emerged as a systemic sensor of lipid and energetic status . This capacity includes components for sensing carbohydrates [202, 203], cholesterol homeostasis through LXRs and FXR, regulation of metabolic rate through TRs, and sensing of diverse lipids by PPARs. Crosstalk within the superfamily ensures that these sensing and regulatory functions integrate with other receptors such as those for sex steroids. Multiple aspects of these relationships are observed in cancer. For example, fatty acids, such as those present in fish oil and a range of other dietary factors, can activate PPARγ and are associated with in vivo prevention of colon cancer in mouse models [165, 204–206] and in human trials in breast cancer . Equally, convergence on PPARs and VDR to regulate IGFBPs and other negative regulatory components of the AKT signaling cascade  provides attractive targets for therapeutic intervention.
To exploit this, understanding in either dietary guidelines for the general population or as a chemoprevention strategy for groups defined at risk (e.g., by age or molecular diagnostic) is highly demanding. Despite the significance and potential clinical benefit of these relationships, it remains unclear the critical time frame and dose range when dietary factors may be protective against cancer development, for example, during embryogenesis, childhood, or adult life. By comparison, considerable resources were required to elucidate what is now established as a clear causal relationship between cigarette smoke and lung cancer . There are reasons to be encouraged in targeting PPARγ in a chemoprevention context as studies on the consequences of long-term usage TZDs in diabetes patients have revealed a protective benefit against lung cancer .
To address the impact of diet on disease, the emerging field of nutrigenomics aims to dissect the impact of dietary factors on genomic regulation, and thereby physiology and pathophysiology, utilizing a range of postgenomic technologies [211, 212]. This level of integration is emerging. For instance, PPARγ polymorphisms recently have been shown to play a role in determining cancer susceptibility only when patients are above a certain body mass index threshold . Exploitation of such understanding will require modeling of these functions in a network context (reviewed in [214, 215]). Most likely, the application of such rational approaches will resolve the significance of PPARs to mediate anticancer actions of potent dietary factors, such as conjugated linoleic acid [130, 216].
5.2. PPARγ and the Regulation of Cellular Energetics
A number of deleterious side effects occur through the use of fatty acids as an energy store, including the generation of reactive oxygen species as a result of lipid peroxidation. The PPAR family combines roles in lipid sensing and utilization with cellular protection against lipid excess. Specifically, PPARγ plays a role in fatty acid uptake and transport (e.g., by adipocytes) and acts to control inflammation that can arise from increased adipocyte differentiation and proliferation (reviewed in [217, 218]). These actions are all altered in malignancy. As proposed by Otto Warburg in the 1930s (and summarized later ), cancer cells derive their energy increasingly from anaerobic glycolysis; this concept has received renewed support in recent years [220–222]. The altered energetics of cancer cells are common events, and cancer patients frequently display symptoms which in many ways mimic type II diabetes . Associated with many of these events is an increased propensity for local inflammation.
PPARγ therapeutics have been explored within these separate arenas in different disease settings. That is, to regulate fatty acid metabolism and insulin resistance within the metabolic syndrome, to suppress inflammation, for example, in colitis models , and to promote mitotic restraint and induce differentiation within cancer cells. These functions are not separated, but rather all distorted within malignancy. The fact that PPARs, in general, and PPARγ specifically play an integrated regulatory role in these processes suggests that new avenues of exploitation will require a more detailed and quantitative understanding of the contribution of PPAR signaling against a tissue and whole body background of inflammation and altered cellular energetics.
5.3. Ongoing Questions
The current challenges in PPARγ cancer biology include the following.(1)Determine at which stage PPARγ can influence normal tissue self-renewal.(2)Understand in cancer systems which combination of critical cellular processes to exploit: exert mitotic restraint, induce differentiation, regulate local inflammation, and impact on cellular energetic processes.(3)Define to what extent conformationally restricted synthetic ligands (the so-called SPARMS ) can regulate target of these cellular processes through selective cohorts of PPARγ target genes.(4)Identify the mechanisms that attenuate, manipulate, dissociate, and redirect PPARγ signaling in cancer cells and address to what extent the proteins involved in these processes are drugable therapeutic targets.(5)Reveal whether this understanding can be best exploited in the setting of either chemoprevention and/or chemotherapy.(6)Quantify, model, and predict to what extent PPARγ is a nodal point within the NR network and other signal transduction process. Establish hierarchies that place PPARγ specifically, and NRs generally, in the context of other signal processes that collectively maintain homeostasis.Abbreviations
|APC:||Adenomatous polyposis coli|
|CAR:||Constitutive androstane receptor|
|CDKI:||Cyclin-dependent kinase inhibitors|
|ERα:||Estrogen receptor α|
|FXR:||Farnesoid X receptor|
|IGFBP:||Insulin-like growth factor binding protein|
|LXR:||Liver X receptor|
|NCOA/SRC:||nNuclear receptor coactivator/steroid receptor coactivator|
|PBP/MED1:||PPARγ binding protein/mediator 1|
|PGC1-α:||Peroxisome proliferator-activated receptor γ coactivator 1 α|
|PPARγ:||Peroxisome proliferator-activated receptor γ|
|PSA:||Prostate specific antigen|
|RAR:||Retinoic acid receptor|
|RXR:||Retinoid X receptor|
|SUMO:||Small ubiquitin-related modifier|
|TNF:||Tumor necrosis factor|
|VDR:||Vitamin D receptor|
Moray J. Campbell acknowledges support of the BBSRC Agri-Foods panel, UK. Carsten Carlberg acknowledges support of the Academy of Finland and the Fonds National de Recherche (Luxembourg). Moray J. Campbell and Carsten Carlberg acknowledge the support of NucSys, a European Community FP6-funded consortium aimed at the dissection and mathematical modeling of nuclear receptor responses to nutritional signals in health and disease. H. Phillip Koeffler acknowledges support of NIH grants. The author is a member of the Jonsson Cancer Center, University of California, Los Angeles, and has the endowed Mark Goodson Chair in Oncology Research at Cedars-Sinai Medical Center. The authors declare that there is no conflict of interest that would prejudice the impartiality.
- P. Tontonoz, R. A. Graves, A. I. Budavari, et al., “Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR and RXR,” Nucleic Acids Research, vol. 22, no. 25, pp. 5628–5634, 1994.
- P. Tontonoz, E. Hu, and B. M. Spiegelman, “Stimulation of adipogenesis in fibroblasts by PPAR2, a lipid-activated transcription factor,” Cell, vol. 79, no. 7, pp. 1147–1156, 1994.
- L. Fajas, J.-C. Fruchart, and J. Auwerx, “PPAR3 mRNA: a distinct PPAR mRNA subtype transcribed from an independent promoter,” FEBS Letters, vol. 438, no. 1-2, pp. 55–60, 1998.
- H. Takano, H. Hasegawa, T. Nagai, and I. Komuro, “The role of PPAR-dependent pathway in the development of cardiac hypertrophy,” Timely Topics in Medicine. Cardiovascular Diseases, vol. 9, p. E10, 2005.
- C. K. Glass, “Going nuclear in metabolic and cardiovascular disease,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 556–560, 2006.
- S. Heikkinen, J. Auwerx, and C. A. Argmann, “PPAR in human and mouse physiology,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 999–1013, 2007.
- B. Staels, “PPAR agonists and the metabolic syndrome,” Therapie, vol. 62, no. 4, pp. 319–326, 2007.
- T. Imai, R. Takakuwa, S. Marchand, et al., “Peroxisome proliferator-activated receptor is required in mature white and brown adipocytes for their survival in the mouse,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 13, pp. 4543–4547, 2004.
- R. T. Gampe Jr., V. G. Montana, M. H. Lambert, et al., “Asymmetry in the PPAR/RXR crystal structure reveals the molecular basis of heterodimerization among nuclear receptors,” Molecular Cell, vol. 5, no. 3, pp. 545–555, 2000.
- J. Li, J. Wang, J. Wang, et al., “Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3,” The EMBO Journal, vol. 19, no. 16, pp. 4342–4350, 2000.
- H.-G. Yoon, D. W. Chan, Z.-Q. Huang, et al., “Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1,” The EMBO Journal, vol. 22, no. 6, pp. 1336–1346, 2003.
- T. Alenghat, J. Yu, and M. A. Lazar, “The N-CoR complex enables chromatin remodeler SNF2H to enhance repression by thyroid hormone receptor,” The EMBO Journal, vol. 25, no. 17, pp. 3966–3974, 2006.
- F. Picard, M. Kurtev, N. Chung, et al., “Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-,” Nature, vol. 429, no. 6993, pp. 771–776, 2004.
- C. Yu, K. Markan, K. A. Temple, D. Deplewski, M. J. Brady, and R. N. Cohen, “The nuclear receptor corepressors N-CoR and SMRT decrease PPAR transcriptional activity and repress 3t3-l1 adipogenesis,” Journal of Biological Chemistry, vol. 28, no. 1, pp. 295–302, 2005.
- I. Takada, M. Mihara, M. Suzawa, et al., “A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR- transactivation,” Nature Cell Biology, vol. 9, no. 11, pp. 1273–1285, 2007.
- K. Ge, Y.-W. Cho, H. Guo, et al., “Alternative mechanisms by which mediator subunit MED1/TRAP220 regulates peroxisome proliferator-activated receptor -stimulated adipogenesis and target gene expression,” Molecular and Cellular Biology, vol. 28, no. 3, pp. 1081–1091, 2008.
- K. Ge, M. Guermah, C.-X. Yuan, et al., “Transcription coactivator TRAP220 is required for PPAR2-stimulated adipogenesis,” Nature, vol. 417, no. 6888, pp. 563–567, 2002.
- P. Puigserver, G. Adelmant, Z. Wu, et al., “Activation of PPAR coactivator-1 through transcription factor docking,” Science, vol. 286, no. 5443, pp. 1368–1371, 1999.
- A. E. Wallberg, S. Yamamura, S. Malik, B. M. Spiegelman, and R. G. Roeder, “Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1,” Molecular Cell, vol. 12, no. 5, pp. 1137–1149, 2003.
- C. Liu, S. Li, T. Liu, J. Borjigin, and J. D. Lin, “Transcriptional coactivator PGC-1 integrates the mammalian clock and energy metabolism,” Nature, vol. 447, no. 7143, pp. 477–481, 2007.
- Y. Zhang, Y. Ba, C. Liu, et al., “PGC-1 induces apoptosis in human epithelial ovarian cancer cells through a PPAR-dependent pathway,” Cell Research, vol. 17, no. 4, pp. 363–373, 2007.
- N. Yadav, D. Cheng, S. Richard, et al., “CARM1 promotes adipocyte differentiation by coactivating PPAR,” EMBO Reports, vol. 9, no. 2, pp. 193–198, 2008.
- R. Métivier, G. Penot, M. R. Hübner, et al., “Estrogen receptor- directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter,” Cell, vol. 115, no. 6, pp. 751–763, 2003.
- G. Reid, M. R. Hübner, R. Métivier, et al., “Cyclic, proteasome-mediated turnover of unliganded and liganded ER on responsive promoters is an integral feature of estrogen signaling,” Molecular Cell, vol. 11, no. 3, pp. 695–707, 2003.
- S. Väisänen, T. W. Dunlop, L. Sinkkonen, C. Frank, and C. Carlberg, “Spatio-temporal activation of chromatin on the human CYP24 gene promoter in the presence of 1,25-dihydroxyvitamin ,” Journal of Molecular Biology, vol. 350, no. 1, pp. 65–77, 2005.
- R. Altmann, M. Hausmann, T. Spöttl, et al., “13-Oxo-ODE is an endogenous ligand for PPAR in human colonic epithelial cells,” Biochemical Pharmacology, vol. 74, no. 4, pp. 612–622, 2007.
- V. Subbarayan, P. Krieg, L. C. Hsi, et al., “15-lipoxygenase-2 gene regulation by its product 15-(S)- hydroxyeicosatetraenoic acid through a negative feedback mechanism that involves peroxisome proliferator-activated receptor ,” Oncogene, vol. 25, no. 44, pp. 6015–6025, 2006.
- V. Subbarayan, X.-C. Xu, J. Kim, et al., “Inverse relationship between 15-lipoxygenase-2 and PPAR- gene expression in normal epithelia compared with tumor epithelia,” Neoplasia, vol. 7, no. 3, pp. 280–293, 2005.
- L. Nagy, P. Tontonoz, J. G. A. Alvarez, H. Chen, and R. M. Evans, “Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR,” Cell, vol. 93, no. 2, pp. 229–240, 1998.
- B. M. Forman, P. Tontonoz, J. Chen, R. P. Brun, B. M. Spiegelman, and R. M. Evans, “15-deoxy--prostaglandin is a ligand for the adipocyte determination factor PPAR,” Cell, vol. 83, no. 5, pp. 803–812, 1995.
- G. Krey, O. Braissant, F. L'Horset, et al., “Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay,” Molecular Endocrinology, vol. 11, no. 6, pp. 779–791, 1997.
- V. Y. Ng, Y. Huang, L. M. Reddy, J. R. Falck, E. T. Lin, and D. L. Kroetz, “Cytochrome P450 eicosanoids are activators of peroxisome proliferator-activated receptor ,” Drug Metabolism and Disposition, vol. 35, no. 7, pp. 1126–1134, 2007.
- S. B. Shappell, R. A. Gupta, S. Manning, et al., “15S-hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor and inhibits proliferation in PC3 prostate carcinoma cells,” Cancer Research, vol. 61, no. 2, pp. 497–503, 2001.
- W.-L. Chou, L.-M. Chuang, C.-C. Chou, et al., “Identification of a novel prostaglandin reductase reveals the involvement of prostaglandin catabolism in regulation of peroxisome proliferator-activated receptor activation,” Journal of Biological Chemistry, vol. 282, no. 25, pp. 18162–18172, 2007.
- A. L. Sabichi, V. Subbarayan, N. Llansa, S. M. Lippman, and D. G. Menter, “Peroxisome proliferator-activated receptor- suppresses cyclooxygenase-2 expression in human prostate cells,” Cancer Epidemiology Biomarkers & Prevention, vol. 13, no. 11, pp. 1704–1709, 2004.
- F. D. Mora, D. K. Jones, P. V. Desai, et al., “Bioassay for the identification of natural product-based activators of peroxisome proliferator-activated receptor- (PPAR): the marine sponge metabolite psammaplin A activates PPAR and induces apoptosis in human breast tumor cells,” Journal of Natural Products, vol. 69, no. 4, pp. 547–552, 2006.
- E. Falcetti, D. M. Flavell, B. Staels, A. Tinker, S. G. Haworth, and L. H. Clapp, “IP receptor-dependent activation of PPAR by stable prostacyclin analogues,” Biochemical and Biophysical Research Communications, vol. 360, no. 4, pp. 821–827, 2007.
- S. Usui, H. Fujieda, T. Suzuki, et al., “Synthesis and evaluation of 2-nonylaminopyridine derivatives as PPAR ligands,” Chemical & Pharmaceutical Bulletin, vol. 55, no. 7, pp. 1053–1059, 2007.
- K. Yamaguchi, S.-H. Lee, T. E. Eling, and S. J. Baek, “A novel peroxisome proliferator-activated receptor ligand, MCC-555, induces apoptosis via posttranscriptional regulation of NAG-1 in colorectal cancer cells,” Molecular Cancer Therapeutics, vol. 5, pp. 1352–1361, 2006.
- I.-L. Lu, C.-F. Huang, Y.-H. Peng, et al., “Structure-based drug design of a novel family of PPAR partial agonists: virtual screening, X-ray crystallography, and in vitro/in vivo biological activities,” Journal of Medicinal Chemistry, vol. 49, no. 9, pp. 2703–2712, 2006.
- T. Fujimura, H. Sakuma, A. Ohkubo-Suzuki, I. Aramori, and S. Mutoh, “Unique properties of coactivator recruitment caused by differential binding of FK614, an anti-diabetic agent, to peroxisome proliferator-activated receptor ,” Chemical & Pharmaceutical Bulletin, vol. 29, no. 3, pp. 423–429, 2006.
- N. Mahindroo, C.-C. Wang, C.-C. Liao, et al., “Indol-1-yl acetic acids as peroxisome proliferator-activated receptor agonists: design, synthesis, structural biology, and molecular docking studies,” Journal of Medicinal Chemistry, vol. 49, no. 3, pp. 1212–1216, 2006.
- E. Burgermeister, A. Schnoebelen, A. Flament, et al., “A novel partial agonist of peroxisome proliferator-activated receptor- (PPAR) recruits PPAR-coactivator-1, prevents triglyceride accumulation, and potentiates insulin signaling in vitro,” Molecular Endocrinology, vol. 20, no. 4, pp. 809–830, 2006.
- T. Tomita, Y. Kakiuchi, and P. S. Tsao, “THR0921, a novel peroxisome proliferator-activated receptor agonist, reduces the severity of collagen-induced arthritis,” Arthritis Research & Therapy, vol. 8, no. 1, article R7, 2006.
- T. Itoh, I. Murota, K. Yoshikai, S. Yamada, and K. Yamamoto, “Synthesis of docosahexaenoic acid derivatives designed as novel PPAR agonists and antidiabetic agents,” Bioorganic & Medicinal Chemistry, vol. 14, no. 1, pp. 98–108, 2006.
- D. W. Salt, B. D. Hudson, L. Banting, M. J. Ellis, and M. G. Ford, “DASH: a novel analysis method for molecular dynamics simulation data. Analysis of ligands of PPAR-,” Journal of Medicinal Chemistry, vol. 48, no. 9, pp. 3214–3220, 2005.
- T. Shiraki, N. Kamiya, S. Shiki, T. S. Kodama, A. Kakizuka, and H. Jingami, “,-unsaturated ketone is a core moiety of natural ligands for covalent binding to peroxisome proliferator-activated receptor ,” Journal of Biological Chemistry, vol. 280, no. 14, pp. 14145–14153, 2005.
- T. Östberg, S. Svensson, G. Selén, et al., “A new class of peroxisome proliferator-activated receptor agonists with a novel binding epitope shows antidiabetic effects,” Journal of Biological Chemistry, vol. 279, no. 39, pp. 41124–41130, 2004.
- M. C. Cho, H. S. Lee, J. H. Kim, et al., “A simple ELISA for screening ligands of peroxisome proliferator-activated receptor ,” Journal of Biochemistry and Molecular Biology, vol. 36, no. 2, pp. 207–213, 2003.
- T. Takagi, Y. Naito, N. Tomatsuri, et al., “Pioglitazone, a PPAR- ligand, provides protection from dextran sulfate sodium-induced colitis in mice in association with inhibition of the NF-B-cytokine cascade,” Redox Report, vol. 7, no. 5, pp. 283–289, 2002.
- S. J. Baek, L. C. Wilson, L. C. Hsi, and T. E. Eling, “Troglitazone, a peroxisome proliferator-activated receptor (PPAR) ligand, selectively induces the early growth response-1 gene independently of PPAR. A novel mechanism for its anti-tumorigenic activity,” Journal of Biological Chemistry, vol. 278, no. 8, pp. 5845–5853, 2003.
- M. Einstein, T. Akiyama, G. Castriota, et al., “The differential interactions of peroxisome proliferator-activated receptor ligands with Tyr473 is a physical basis for their unique biological activities,” Molecular Pharmacology, vol. 73, pp. 62–74, 2008.
- T. Fujimura, H. Sakuma, S. Konishi, et al., “FK614, a novel peroxisome proliferator-activated receptor modulator, induces differential transactivation through a unique ligand-specific interaction with transcriptional coactivators,” Journal of Pharmacological Sciences, vol. 99, no. 4, pp. 342–352, 2005.
- T. Shiraki, T. S. Kodama, H. Jingami, and N. Kamiya, “Rational discovery of a novel interface for a coactivator in the peroxisome proliferator-activated receptor : theoretical implications of impairment in type diabetes mellitus,” Proteins, vol. 58, no. 2, pp. 418–425, 2005.
- A. Elbrecht, Y. Chen, A. Adams, et al., “L-764406 is a partial agonist of human peroxisome proliferator-activated receptor . The role of in ligand binding,” Journal of Biological Chemistry, vol. 274, no. 12, pp. 7913–7922, 1999.
- B. Zhang, J. Berger, G. Zhou, et al., “Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor ,” Journal of Biological Chemistry, vol. 271, no. 50, pp. 31771–31774, 1996.
- B. Pourcet, J.-C. Fruchart, B. Staels, and C. Glineur, “Selective PPAR modulators, dual and pan PPAR agonists: multimodal drugs for the treatment of type 2 diabetes and atherosclerosis,” Expert Opinion on Emerging Drugs, vol. 11, no. 3, pp. 379–401, 2006.
- F. Molnár, M. Matilainen, and C. Carlberg, “Structural determinants of the agonist-independent association of human peroxisome proliferator-activated receptors with coactivators,” Journal of Biological Chemistry, vol. 280, no. 28, pp. 26543–26556, 2005.
- M. Sandri, J. Lin, C. Handschin, et al., “PGC-1 protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 44, pp. 16260–16265, 2006.
- C. Handschin and B. M. Spiegelman, “Peroxisome proliferator-activated receptor coactivator 1 coactivators, energy homeostasis, and metabolism,” Endocrine Reviews, vol. 27, no. 7, pp. 728–735, 2006.
- M. Sano, S. Tokudome, N. Shimizu, et al., “Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor coactivator 1,” Journal of Biological Chemistry, vol. 282, no. 35, pp. 25970–25980, 2007.
- D. Yamashita, T. Yamaguchi, M. Shimizu, N. Nakata, F. Hirose, and T. Osumi, “The transactivating function of peroxisome proliferator-activated receptor is negatively regulated by SUMO conjugation in the amino-terminal domain,” Genes to Cells, vol. 9, no. 11, pp. 1017–1029, 2004.
- G. Pascual, A. L. Fong, S. Ogawa, et al., “A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-,” Nature, vol. 437, no. 7059, pp. 759–763, 2005.
- S. J. Choi, S. S. Chung, E. J. Rho, et al., “Negative modulation of RXR transcriptional activity by small ubiquitin-related modifier (SUMO) modification and its reversal by sumo-specific protease susp1,” Journal of Biological Chemistry, vol. 281, no. 41, pp. 30669–30677, 2006.
- E. Burgermeister and R. Seger, “MAPK kinases as nucleo-cytoplasmic shuttles for PPAR,” Cell Cycle, vol. 6, no. 13, pp. 1539–1548, 2007.
- E. Burgermeister, D. Chuderland, T. Hanoch, M. Meyer, M. Liscovitch, and R. Seger, “Interaction with MEK causes nuclear export and downregulation of peroxisome proliferator-activated receptor ,” Molecular and Cellular Biology, vol. 27, no. 3, pp. 803–817, 2007.
- R. Yin, Y. G. Dong, and H. L. Li, “PPAR phosphorylation mediated by JNK MAPK: a potential role in macrophage-derived foam cell formation,” Acta Pharmacologica Sinica, vol. 27, no. 9, pp. 1146–1152, 2006.
- P. Misra, E. D. Owuor, W. Li, et al., “Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP). Stimulation of transcriptional regulation by mitogen-activated protein kinase,” Journal of Biological Chemistry, vol. 277, no. 50, pp. 48745–48754, 2002.
- A. L. Bookout, Y. Jeong, M. Downes, R. T. Yu, R. M. Evans, and D. J. Mangelsdorf, “Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network,” Cell, vol. 126, no. 4, pp. 789–799, 2006.
- X. Yang, M. Downes, R. T. Yu, et al., “Nuclear receptor expression links the circadian clock to metabolism,” Cell, vol. 126, no. 4, pp. 801–810, 2006.
- R. J. Perera, E. G. Marcusson, S. Koo, et al., “Identification of novel PPAR target genes in primary human adipocytes,” Gene, vol. 369, pp. 90–99, 2006.
- C. P. Hodgkinson and S. Ye, “Microarray analysis of peroxisome proliferator-activated receptor- induced changes in gene expression in macrophages,” Biochemical and Biophysical Research Communications, vol. 308, no. 3, pp. 505–510, 2003.
- S. Vignati, V. Albertini, A. Rinaldi, et al., “Cellular and molecular consequences of peroxisome proliferator-activated receptor- activation in ovarian cancer cells,” Neoplasia, vol. 8, no. 10, pp. 851–861, 2006.
- Z. N. Shen, K. Nishida, H. Doi, et al., “Suppression of chondrosarcoma cells by 15-deoxy--prostaglandin is associated with altered expression of Bax/Bcl-xL and p21,” Biochemical and Biophysical Research Communications, vol. 328, no. 2, pp. 375–382, 2005.
- T. Suzuki, S. Hayashi, Y. Miki, et al., “Peroxisome proliferator-activated receptor in human breast carcinoma: a modulator of estrogenic actions,” Endocrine-Related Cancer, vol. 13, no. 1, pp. 233–250, 2006.
- B. Lecka-Czernik, C. Ackert-Bicknell, M. L. Adamo, et al., “Activation of peroxisome proliferator-activated receptor (PPAR) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo,” Endocrinology, vol. 148, no. 2, pp. 903–911, 2007.
- T. Degenhardt, M. Matilainen, K.-H. Herzig, T. W. Dunlop, and C. Carlberg, “The insulin-like growth factor-binding protein 1 gene is a primary target of peroxisome proliferator-activated receptors,” Journal of Biological Chemistry, vol. 281, no. 51, pp. 39607–39619, 2006.
- R. A. Gupta, J. A. Brockman, P. Sarraf, T. M. Willson, and R. N. DuBois, “Target genes of peroxisome proliferator-activated receptor in colorectal cancer cells,” Journal of Biological Chemistry, vol. 276, no. 32, pp. 29681–29687, 2001.
- F. Zandbergen, S. Mandard, P. Escher, et al., “The switch gene 2 is a novel PPAR target gene,” Biochemical Journal, vol. 392, no. 2, pp. 313–324, 2005.
- D. Bruemmer, F. Yin, J. Liu, et al., “Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor in vascular smooth muscle cells,” Circulation Research, vol. 93, no. 4, pp. e38–e47, 2003.
- C. Han, A. J. Demetris, G. K. Michalopoulos, Q. Zhan, J. H. Shelhamer, and T. Wu, “PPAR ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and pathway,” Hepatology, vol. 38, no. 1, pp. 167–177, 2003.
- Y. Yasui, M. Hosokawa, T. Sahara, et al., “Bitter gourd seed fatty acid rich in 9c,11t,13t-conjugated linolenic acid induces apoptosis and up-regulates the GADD45, p53 and PPAR in human colon cancer Caco-2 cells,” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 73, no. 2, pp. 113–119, 2005.
- R. Nielsen, L. Grøntved, H. G. Stunnenberg, and S. Mandrup, “Peroxisome proliferator-activated receptor subtype- and cell-type-specific activation of genomic target genes upon adenoviral transgene delivery,” Molecular and Cellular Biology, vol. 26, no. 15, pp. 5698–5714, 2006.
- I. Szatmari, A. Pap, R. Ruhl, et al., “PPAR controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells,” Journal of Experimental Medicine, vol. 203, no. 10, pp. 2351–2362, 2006.
- X. Dai, K. Sayama, Y. Shirakata, et al., “PPAR is an important transcription factor in 1,25-dihydroxyvitamin D3-induced involucrin expression,” Journal of Dermatological Science, vol. 50, no. 1, pp. 53–60, 2008.
- O. Ziouzenkova and J. Plutzky, “Retinoid metabolism and nuclear receptor responses: new insights into coordinated regulation of the PPAR-RXR complex,” FEBS Letters, vol. 582, no. 1, pp. 32–38, 2008.
- J. S. Carroll, C. A. Meyer, J. Song, et al., “Genome-wide analysis of estrogen receptor binding sites,” Nature Genetics, vol. 38, no. 11, pp. 1289–1297, 2006.
- M. Heinäniemi, J. O. Uski, T. Degenhardt, and C. Carlberg, “Meta-analysis of primary target genes of peroxisome proliferator-activated receptors,” Genome Biology, vol. 8, no. 7, article R147, 2007.
- D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000.
- M. Shackleton, F. Vaillant, K. J. Simpson, et al., “Generation of a functional mammary gland from a single stem cell,” Nature, vol. 439, no. 7072, pp. 84–88, 2006.
- J. Stingl, P. Eirew, I. Ricketson, et al., “Purification and unique properties of mammary epithelial stem cells,” Nature, vol. 439, no. 7079, pp. 993–997, 2006.
- G. D. Richardson, C. N. Robson, S. H. Lang, D. E. Neal, N. J. Maitland, and A. T. Collins, “CD133, a novel marker for human prostatic epithelial stem cells,” Journal of Cell Science, vol. 117, no. 16, pp. 3539–3545, 2004.
- S. Rizzo, G. Attard, and D. L. Hudson, “Prostate epithelial stem cells,” Cell Proliferation, vol. 38, no. 6, pp. 363–374, 2005.
- N. Barker, J. H. van Es, J. Kuipers, et al., “Identification of stem cells in small intestine and colon by marker gene Lgr5,” Nature, vol. 449, no. 7165, pp. 1003–1007, 2007.
- M. J. Kiel, S. He, R. Ashkenazi, et al., “Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU,” Nature, vol. 449, no. 7159, pp. 238–242, 2007.
- P. M. Lansdorp, “Immortal strands? Give me a break,” Cell, vol. 129, no. 7, pp. 1244–1247, 2007.
- M. J. Conboy, A. O. Karasov, and T. A. Rando, “High incidence of non-random template strand segregation and asymmetric fate determination in dividing stem cells and their progeny,” PLoS Biology, vol. 5, no. 5, p. e102, 2007.
- V. Shinin, B. Gayraud-Morel, D. Gomès, and S. Tajbakhsh, “Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells,” Nature Cell Biology, vol. 8, no. 7, pp. 677–682, 2006.
- P. Karpowicz, C. Morshead, A. Kam, et al., “Support for the immortal strand hypothesis: neural stem cells partition DNA asymmetrically in vitro,” Journal of Cell Biology, vol. 170, no. 5, pp. 721–732, 2005.
- S. A. Roberts, J. H. Hendry, and C. S. Potten, “Intestinal crypt clonogens: a new interpretation of radiation survival curve shape and clonogenic cell number,” Cell Proliferation, vol. 36, no. 4, pp. 215–231, 2003.
- L. Rambhatla, S. Ram-Mohan, J. J. Cheng, and J. L. Sherley, “Immortal DNA strand cosegregation requires p53/IMPDH-dependent asymmetric self-renewal associated with adult stem cells,” Cancer Research, vol. 65, no. 8, pp. 3155–3161, 2005.
- J. Cairns, “Mutation selection and the natural history of cancer,” Nature, vol. 255, no. 5505, pp. 197–200, 1975.
- C. S. Potten, W. J. Hume, P. Reid, and J. Cairns, “The segregation of DNA in epithelial stem cells,” Cell, vol. 15, no. 3, pp. 899–906, 1978.
- M. Al-Hajj, M. W. Becker, M. Wicha, I. Weissman, and M. F. Clarke, “Therapeutic implications of cancer stem cells,” Current Opinion in Genetics & Development, vol. 14, no. 1, pp. 43–47, 2004.
- T. Setoguchi, T. Taga, and T. Kondo, “Cancer stem cells persist in many cancer cell lines,” Cell Cycle, vol. 3, no. 4, pp. 414–415, 2004.
- A. T. Collins, P. A. Berry, C. Hyde, M. J. Stower, and N. J. Maitland, “Prospective identification of tumorigenic prostate cancer stem cells,” Cancer Research, vol. 65, no. 23, pp. 10946–10951, 2005.
- C. A. O'Brien, A. Pollett, S. Gallinger, and J. E. Dick, “A human colon cancer cell capable of initiating tumour growth in immunodeficient mice,” Nature, vol. 445, no. 7123, pp. 106–110, 2007.
- M. S. Wicha, S. Liu, and G. Dontu, “Cancer stem cells: an old idea—a paradigm shift,” Cancer Research, vol. 66, no. 4, pp. 1883–1890, 2006.
- P. Tontonoz, S. Singer, B. M. Forman, et al., “Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor and the retinoid X receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 1, pp. 237–241, 1997.
- E. Elstner, C. Müller, K. Koshizuka, et al., “Ligands for peroxisome proliferator-activated receptor and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 15, pp. 8806–8811, 1998.
- E. Mueller, P. Sarraf, P. Tontonoz, et al., “Terminal differentiation of human breast cancer through PPAR,” Molecular Cell, vol. 1, no. 3, pp. 465–470, 1998.
- R. Butler, S. H. Mitchell, D. J. Tindall, and C. Y. Young, “Nonapoptotic cell death associated with S-phase arrest of prostate cancer cells via the peroxisome proliferator-activated receptor ligand, 15-deoxy--prostaglandin ,” Cell Growth & Differentiation, vol. 11, no. 1, pp. 49–61, 2000.
- W. G. Jiang, A. Redfern, R. P. Bryce, and R. E. Mansel, “Peroxisome proliferator activated receptor- (PPAR-) mediates the action of gamma linolenic acid in breast cancer cells,” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 62, no. 2, pp. 119–127, 2000.
- R. G. Mehta, E. Williamson, M. K. Patel, and H. P. Koeffler, “A ligand of peroxisome proliferator-activated receptor , retinoids, and prevention of preneoplastic mammary lesions,” Journal of the National Cancer Institute, vol. 92, no. 5, pp. 418–423, 2000.
- E. Mueller, M. Smith, P. Sarraf, et al., “Effects of ligand activation of peroxisome proliferator-activated receptor in human prostate cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 20, pp. 10990–10995, 2000.
- K.-I. Nakashiro, Y. Hayashi, A. Kita, et al., “Role of peroxisome proliferator-activated receptor and its ligands in non-neoplastic and neoplastic human urothelial cells,” American Journal of Pathology, vol. 159, no. 2, pp. 591–597, 2001.
- M. R. Smith and P. W. Kantoff, “Peroxisome proliferator-activated receptor (PPAR) as a novel target for prostate cancer,” Investigational New Drugs, vol. 20, no. 2, pp. 195–200, 2002.
- L. Jackson, W. Wahli, L. Michalik, et al., “Potential role for peroxisome proliferator activated receptor (PPAR) in preventing colon cancer,” Gut, vol. 52, no. 9, pp. 1317–1322, 2003.
- C. Qin, R. Burghardt, R. Smith, M. Wormke, J. Stewart, and S. Safe, “Peroxisome proliferator-activated receptor agonists induce proteasome-dependent degradation of cyclin D1 and estrogen receptor in MCF-7 breast cancer cells,” Cancer Research, vol. 63, no. 5, pp. 958–964, 2003.
- Y. Xu, S. Iyengar, R. L. Roberts, S. B. Shappell, and D. M. Peehl, “Primary culture model of peroxisome proliferator-activated receptor activity in prostate cancer cells,” Journal of Cellular Physiology, vol. 196, no. 1, pp. 131–143, 2003.
- R. Yoshimura, M. Matsuyama, Y. Segawa, et al., “Expression of peroxisome proliferator-activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists,” International Journal of Cancer, vol. 104, no. 5, pp. 597–602, 2003.
- J. Lu, K. Imamura, S. Nomura, et al., “Chemopreventive effect of peroxisome proliferator-activated receptor on gastric carcinogenesis in mice,” Cancer Research, vol. 65, no. 11, pp. 4769–4774, 2005.
- S. K. Radhakrishnan and A. L. Gartel, “The PPAR- agonist pioglitazone post-transcriptionally induces p21 in PC3 prostate cancer but not in other cell lines,” Cell Cycle, vol. 4, no. 4, pp. 582–584, 2005.
- R. M. Cesario, J. Stone, W. C. Yen, R. P. Bissonnette, and W. W. Lamph, “Differentiation and growth inhibition mediated via the RXR:PPAR heterodimer in colon cancer,” Cancer Letters, vol. 240, no. 2, pp. 225–233, 2006.
- W. Kassouf, S. Chintharlapalli, M. Abdelrahim, G. Nelkin, S. Safe, and A. M. Kamat, “Inhibition of bladder tumor growth by 1,1-bis(-indolyl)-1-(-substitutedphenyl)methanes: a new class of peroxisome proliferator-activated receptor agonists,” Cancer Research, vol. 66, no. 1, pp. 412–418, 2006.
- C. J. Lee, J. S. Han, C. Y. Seo, et al., “Pioglitazone, a synthetic ligand for PPAR, induces apoptosis in RB-deficient human colorectal cancer cells,” Apoptosis, vol. 11, no. 3, pp. 401–411, 2006.
- M. Y. Li, T. W. Lee, A. P. Yim, and G. G. Chen, “Function of PPAR and its ligands in lung cancer,” Critical Reviews in Clinical Laboratory Sciences, vol. 43, pp. 183–202, 2006.
- S. Nakata, T. Yoshida, T. Shiraishi, et al., “15-deoxy--prostaglandin induces death receptor 5 expression through mRNA stabilization independently of PPAR and potentiates trail-induced apoptosis,” Molecular Cancer Therapeutics, vol. 5, no. 7, pp. 1827–1835, 2006.
- N. P. Núñez, H. Liu, and G. G. Meadows, “PPAR- ligands and amino acid deprivation promote apoptosis of melanoma, prostate, and breast cancer cells,” Cancer Letters, vol. 236, no. 1, pp. 133–141, 2006.
- C. Bocca, F. Bozzo, S. Francica, S. Colombatto, and A. Miglietta, “Involvement of PPAR and E-cadherin/-catenin pathway in the antiproliferative effect of conjugated linoleic acid in MCF-7 cells,” International Journal of Cancer, vol. 121, no. 2, pp. 248–256, 2007.
- K. Y. Kim, J. H. Ahn, and H. G. Cheon, “Apoptotic action of peroxisome proliferator-activated receptor- activation in human non small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation,” Molecular Pharmacology, vol. 72, no. 3, pp. 674–685, 2007.
- M. S. Lin, W. C. Chen, X. Bai, and Y. D. Wang, “Activation of peroxisome proliferator-activated receptor inhibits cell growth via apoptosis and arrest of the cell cycle in human colorectal cancer,” Journal of Digestive Diseases, vol. 8, no. 2, pp. 82–88, 2007.
- D.-H. Nam, S. Ramachandran, D.-K. Song, et al., “Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR ligand ciglitizone,” Molecular Human Reproduction, vol. 13, no. 11, pp. 829–836, 2007.
- T. Shigeto, Y. Yokoyama, B. Xin, and H. Mizunuma, “Peroxisome proliferator-activated receptor and ligands inhibit the growth of human ovarian cancer,” Oncology Reports, vol. 18, no. 4, pp. 833–840, 2007.
- Y. Su, K. Vanderlaag, C. Ireland, et al., “1,1-bis(-indolyl)-1-(-biphenyl)methane inhibits basal-like breast cancer growth in athymic nude mice,” Breast Cancer Research, vol. 9, no. 4, article R56, 2007.
- Y.-C. Yang, Y.-P. Tsao, T.-C. Ho, and I.-P. Choung, “Peroxisome proliferator-activated receptor- agonists cause growth arrest and apoptosis in human ovarian carcinoma cell lines,” International Journal of Gynecological Cancer, vol. 17, no. 2, pp. 418–425, 2007.
- T. Servidei, R. Morosetti, C. Ferlini, et al., “The cellular response to PPAR ligands is related to the phenotype of neuroblastoma cell lines,” Oncology Research, vol. 14, no. 7-8, pp. 345–354, 2004.
- R. Morosetti, T. Servidei, M. Mirabella, et al., “The PPAR ligands PG and rosiglitazone show a differential ability to inhibit proliferation and to induce apoptosis and differentiation of human glioblastoma cell lines,” International Journal of Oncology, vol. 25, no. 2, pp. 493–502, 2004.
- M. Konopleva, E. Elstner, T. J. McQueen, et al., “Peroxisome proliferator-activated receptor and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias,” Molecular Cancer Therapeutics, vol. 3, no. 10, pp. 1249–1262, 2004.
- Y.-R. Lee, H.-N. Yu, E.-M. Noh, et al., “Peroxisome proliferator-activated receptor and retinoic acid receptor synergistically up-regulate the tumor suppressor PTEN in human promyeloid leukemia cells,” International Journal of Hematology, vol. 85, no. 3, pp. 231–237, 2007.
- E. Saez, P. Tontonoz, M. C. Nelson, et al., “Activators of the nuclear receptor PPAR enhance colon polyp formation,” Nature Medicine, vol. 4, no. 9, pp. 1058–1061, 1998.
- C. A. McAlpine, Y. Barak, I. Matise, and R. T. Cormier, “Intestinal-specific PPAR deficiency enhances tumorigenesis in mice,” International Journal of Cancer, vol. 119, no. 10, pp. 2339–2346, 2006.
- S. Wei, L.-F. Lin, C.-C. Yang, et al., “Thiazolidinediones modulate the expression of -catenin and other cell-cycle regulatory proteins by targeting the F-box proteins of Skp1-Cul1-F-box protein E3 ubiquitin ligase independently of peroxisome proliferator-activated receptor ,” Molecular Pharmacology, vol. 72, no. 3, pp. 725–733, 2007.
- J.-R. Weng, C.-Y. Chen, J. J. Pinzone, M. D. Ringel, and C.-S. Chen, “Beyond peroxisome proliferator-activated receptor signaling: the multi-facets of the antitumor effect of thiazolidinediones,” Endocrine-Related Cancer, vol. 13, no. 2, pp. 401–413, 2006.
- J.-W. Huang, C.-W. Shiau, Y.-T. Yang, et al., “Peroxisome proliferator-activated receptor -independent ablation of cyclin D1 by thiazolidinediones and their derivatives in breast cancer cells,” Molecular Pharmacology, vol. 67, no. 4, pp. 1342–1348, 2005.
- E. Å. Jansson, A. Are, G. Greicius, et al., “The Wnt/-catenin signaling pathway targets PPAR activity in colon cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 5, pp. 1460–1465, 2005.
- M. G. Posch, C. Zang, W. Mueller, U. Lass, A. von Deimling, and E. Elstner, “Somatic mutations in peroxisome proliferator-activated receptor- are rare events in human cancer cells,” Medical Science Monitor, vol. 10, no. 8, pp. BR250–BR254, 2004.
- M. L. Slattery, K. Curtin, R. Wolff, et al., “PPAR and colon and rectal cancer: associations with specific tumor mutations, aspirin, ibuprofen and insulin-related genes (United States),” Cancer Causes and Control, vol. 17, no. 3, pp. 239–249, 2006.
- A. W. Bull, K. R. Steffensen, J. Leers, and J. J. Rafter, “Activation of PPAR in colon tumor cell lines by oxidized metabolites of linoleic acid, endogenous ligands for PPAR ,” Carcinogenesis, vol. 24, no. 11, pp. 1717–1722, 2003.
- S. Chintharlapalli, S. Papineni, and S. Safe, “1,1-Bis(-indolyl)-1-(-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through PPAR-dependent and PPAR-independent pathways,” Molecular Cancer Therapeutics, vol. 5, no. 5, pp. 1362–1370, 2006.
- T. Yoshizumi, T. Ohta, I. Ninomiya, et al., “Thiazolidinedione, a peroxisome proliferator-activated receptor- ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects,” International Journal of Oncology, vol. 25, no. 3, pp. 631–639, 2004.
- K. Yamazaki, M. Shimizu, M. Okuno, et al., “Synergistic effects of RXR and PPAR ligands to inhibit growth in human colon cancer cells—phosphorylated RXR is a critical target for colon cancer management,” Gut, vol. 56, no. 11, pp. 1557–1563, 2007.
- A. J. Chang, D. H. Song, and M. M. Wolfe, “Attenuation of peroxisome proliferator-activated receptor (PPAR) mediates gastrin-stimulated colorectal cancer cell proliferation,” Journal of Biological Chemistry, vol. 281, no. 21, pp. 14700–14710, 2006.
- W. de Lau, N. Barker, and H. Clevers, “Wnt signaling in the normal intestine and colorectal cancer,” Frontiers in Bioscience, vol. 12, no. 2, pp. 471–491, 2007.
- N. Suh, Y. Wang, C. R. Williams, et al., “A new ligand for the peroxisome proliferator-activated receptor- (PPAR-), GW7845, inhibits rat mammary carcinogenesis,” Cancer Research, vol. 59, no. 22, pp. 5671–5673, 1999.
- C. J. Nicol, M. Yoon, J. M. Ward, et al., “PPAR influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis,” Carcinogenesis, vol. 25, no. 9, pp. 1747–1755, 2004.
- E. Saez, J. Rosenfeld, A. Livolsi, et al., “PPAR signaling exacerbates mammary gland tumor development,” Genes & Development, vol. 18, no. 5, pp. 528–540, 2004.
- M. W. Kilgore, P. L. Tate, S. Rai, E. Sengoku, and T. M. Price, “MCF-7 and T47D human breast cancer cells contain a functional peroxisomal response,” Molecular and Cellular Endocrinology, vol. 129, no. 2, pp. 229–235, 1997.
- E. Elstner, E. A. Williamson, C. Zang, et al., “Novel therapeutic approach: ligands for PPAR and retinoid receptors induce apoptosis in Bcl-2-positive human breast cancer cells,” Breast Cancer Research and Treatment, vol. 74, no. 2, pp. 155–165, 2002.
- D. L. Crowe and R. A. Chandraratna, “A retinoid X receptor (RXR)-selective retinoid reveals that RXR- is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands,” Breast Cancer Research, vol. 6, no. 5, pp. R546–R555, 2004.
- J. M. Seargent, E. A. Yates, and J. H. Gill, “GW9662, a potent antagonist of PPAR, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPAR agonist rosiglitazone, independently of PPAR activation,” British Journal of Pharmacology, vol. 143, no. 8, pp. 933–937, 2004.
- M. H. Jarrar and A. Baranova, “PPAR activation by thiazolidinediones (TZDs) may modulate breast carcinoma outcome: the importance of interplay with TGF signalling,” Journal of Cellular and Molecular Medicine, vol. 11, no. 1, pp. 71–87, 2007.
- M. Mody, N. Dharker, M. Bloomston, et al., “Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-, CH11 and CYC202,” Endocrine-Related Cancer, vol. 14, no. 2, pp. 305–315, 2007.
- S. Y. James, F. Lin, S. K. Kolluri, M. I. Dawson, and X.-K. Zhang, “Regulation of retinoic acid receptor expression by peroxisome proliferator-activated receptor ligands in cancer cells,” Cancer Research, vol. 63, no. 13, pp. 3531–3538, 2003.
- H. Sun, I. M. Berquin, and I. J. Edwards, “Omega-3 polyunsaturated fatty acids regulate syndecan-1 expression in human breast cancer cells,” Cancer Research, vol. 65, no. 10, pp. 4442–4447, 2005.
- H.-J. Kim, J.-Y. Kim, Z. Meng, et al., “15-deoxy--prostaglandin inhibits transcriptional activity of estrogen receptor- via covalent modification of DNA-binding domain,” Cancer Research, vol. 67, no. 6, pp. 2595–2602, 2007.
- I. Papadaki, E. Mylona, I. Giannopoulou, S. Markaki, A. Keramopoulos, and L. Nakopoulou, “PPAR expression in breast cancer: clinical value and correlation with ER,” Histopathology, vol. 46, no. 1, pp. 37–42, 2005.
- H. J. Burstein, G. D. Demetri, E. Mueller, P. Sarraf, B. M. Spiegelman, and E. P. Winer, “Use of the peroxisome proliferator-activated receptor (PPAR) ligand troglitazone as treatment for refractory breast cancer: a phase II study,” Breast Cancer Research and Treatment, vol. 79, no. 3, pp. 391–397, 2003.
- M. W. Goldblatt, “Properties of human seminal plasma,” Journal of Physiology, vol. 84, no. 2, pp. 208–218, 1935.
- J. Kim, P. Yang, M. Suraokar, et al., “Suppression of prostate tumor cell growth by stromal cell prostaglandin D synthase-derived products,” Cancer Research, vol. 65, no. 14, pp. 6189–6198, 2005.
- T. Kubota, K. Koshizuka, E. A. Williamson, et al., “Ligand for peroxisome proliferator-activated receptor (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo,” Cancer Research, vol. 58, no. 15, pp. 3344–3352, 1998.
- C.-W. Shiau, C.-C. Yang, S. K. Kulp, et al., “Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPAR,” Cancer Research, vol. 65, no. 4, pp. 1561–1569, 2005.
- C.-C. Yang, C.-Y. Ku, S. Wei, et al., “Peroxisome proliferator-activated receptor -independent repression of prostate-specific antigen expression by thiazolidinediones in prostate cancer cells,” Molecular Pharmacology, vol. 69, no. 5, pp. 1564–1570, 2006.
- E. Saez, P. Olson, and R. M. Evans, “Genetic deficiency in Pparg does not alter development of experimental prostate cancer,” Nature Medicine, vol. 9, no. 10, pp. 1265–1266, 2003.
- H. Asou, W. Verbeek, E. Williamson, et al., “Growth inhibition of myeloid leukemia cells by troglitazone, a ligand for peroxisome proliferator activated receptor , and retinoids,” International Journal of Oncology, vol. 15, no. 5, pp. 1027–1031, 1999.
- T. Kumagai, T. Ikezoe, D. Gui, et al., “RWJ-241947 (MCC-555), a unique peroxisome proliferator-activated receptor- ligand with antitumor activity against human prostate cancer in vitro and in Beige/Nude/X-linked immunodeficient mice and enhancement of apoptosis in myeloma cells induced by arsenic trioxide,” Clinical Cancer Research, vol. 10, no. 4, pp. 1508–1520, 2004.
- L. H. Wang, X. Y. Yang, X. Zhang, et al., “Transcriptional inactivation of STAT3 by PPAR suppresses IL-6-responsive multiple myeloma cells,” Immunity, vol. 20, no. 2, pp. 205–218, 2004.
- H. Liu, C. Zang, M. H. Fenner, et al., “Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPAR/ ligand TZD18,” Blood, vol. 107, no. 9, pp. 3683–3692, 2006.
- D. Bouancheau, A. Jarry, S. Mottier, et al., “Low expression of ORF4, a dominant negative variant of peroxisome proliferator-activated receptor , in colorectal adenocarcinoma,” Oncology Reports, vol. 18, no. 2, pp. 489–495, 2007.
- X. Wang, R. C. Southard, and M. W. Kilgore, “The increased expression of peroxisome proliferator-activated receptor-1 in human breast cancer is mediated by selective promoter usage,” Cancer Research, vol. 64, no. 16, pp. 5592–5596, 2004.
- V. Subbarayan, A. L. Sabichi, J. Kim, et al., “Differential peroxisome proliferator-activated receptor- isoform expression and agonist effects in normal and malignant prostate cells,” Cancer Epidemiology Biomarkers & Prevention, vol. 13, no. 11, pp. 1710–1716, 2004.
- L. Sabatino, A. Casamassimi, G. Peluso, et al., “A novel peroxisome proliferator-activated receptor isoform with dominant negative activity generated by alternative splicing,” Journal of Biological Chemistry, vol. 280, no. 28, pp. 26517–26525, 2005.
- C. Fiatte, C. Huin, I. Bertin, et al., “Genetic analysis of peroxisome proliferator-activated receptor 1 splice variants in human colorectal cell lines,” International Journal of Oncology, vol. 29, no. 6, pp. 1601–1610, 2006.
- T. G. Kroll, P. Sarraf, L. Pecciarini, et al., “- fusion oncogene in human thyroid carcinoma (Science (August 25) (1357)),” Science, vol. 289, no. 5484, pp. 1357–1360, 2000.
- G. Watkins, A. Douglas-Jones, R. E. Mansel, and W. G. Jiang, “The localisation and reduction of nuclear staining of PPAR and PGC-1 in human breast cancer,” Oncology Reports, vol. 12, no. 2, pp. 483–488, 2004.
- J. Feilchenfeldt, M.-A. Bründler, C. Soravia, M. Tötsch, and C. A. Meier, “Peroxisome proliferator-activated receptors (PPARs) and associated transcription factors in colon cancer: reduced expression of PPAR-coactivator 1 (PGC-1),” Cancer Letters, vol. 203, no. 1, pp. 25–33, 2004.
- F. L. Khanim, L. M. Gommersall, V. H. J. Wood, et al., “Altered SMRT levels disrupt vitamin receptor signalling in prostate cancer cells,” Oncogene, vol. 23, no. 40, pp. 6712–6725, 2004.
- T.-H. Chang and E. Szabo, “Enhanced growth inhibition by combination differentiation therapy with ligands of peroxisome proliferator-activated receptor- and inhibitors of histone deacetylase in adenocarcinoma of the lung,” Clinical Cancer Research, vol. 8, no. 4, pp. 1206–1212, 2002.
- J.-S. Annicotte, I. Iankova, S. Miard, et al., “Peroxisome proliferator-activated receptor regulates E-cadherin expression and inhibits growth and invasion of prostate cancer,” Molecular and Cellular Biology, vol. 26, no. 20, pp. 7561–7574, 2006.
- A. Lal, A. E. Lash, S. F. Altschul, et al., “A public database for gene expression in human cancers,” Cancer Research, vol. 59, no. 21, pp. 5403–5407, 1999.
- M. Fu, M. Rao, T. Bouras, et al., “Cyclin D1 inhibits peroxisome proliferator-activated receptor -mediated adipogenesis through histone deacetylase recruitment,” Journal of Biological Chemistry, vol. 280, no. 17, pp. 16934–16941, 2005.
- D. Bonofiglio, S. Gabriele, S. Aquila, et al., “Estrogen receptor binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor signaling in breast cancer cells,” Clinical Cancer Research, vol. 11, no. 17, pp. 6139–6147, 2005.
- M. Yuri, T. Sasahira, K. Nakai, S. Ishimaru, H. Ohmori, and H. Kuniyasu, “Reversal of expression of 15-lipoxygenase-1 to cyclooxygenase-2 is associated with development of colonic cancer,” Histopathology, vol. 51, no. 4, pp. 520–527, 2007.
- A. Gustafsson, E. Hansson, U. Kressner, et al., “ subtype, COX and PPAR receptor expression in colorectal cancer in prediction of disease-specific mortality,” International Journal of Cancer, vol. 121, no. 2, pp. 232–240, 2007.
- M. C. Byrns, S. Steckelbroeck, and T. M. Penning, “An indomethacin analogue, -(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3-HSD, type 5 17-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies,” Biochemical Pharmacology, vol. 75, no. 2, pp. 484–493, 2008.
- K.-M. Fung, E. N. S. Samara, C. Wong, et al., “Increased expression of type 2 3-hydroxysteroid dehydrogenase/type 5 17-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma,” Endocrine-Related Cancer, vol. 13, no. 1, pp. 169–180, 2006.
- A. L. Lovering, J. P. Ride, C. M. Bunce, J. C. Desmond, S. M. Cummings, and S. A. White, “Crystal structures of prostaglandin 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin,” Cancer Research, vol. 64, no. 5, pp. 1802–1810, 2004.
- J. C. Desmond, J. C. Mountford, M. T. Drayson, et al., “The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs,” Cancer Research, vol. 63, no. 2, pp. 505–512, 2003.
- K. Matsuura, H. Shiraishi, A. Hara, et al., “Identification of a principal mRNA species for human 3-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin 11-ketoreductase activity,” Journal of Biochemistry, vol. 124, no. 5, pp. 940–946, 1998.
- S. D. Hursting, L. M. Lashinger, L. H. Colbert, et al., “Energy balance and carcinogenesis: underlying pathways and targets for intervention,” Current Cancer Drug Targets, vol. 7, no. 5, pp. 484–491, 2007.
- R. M. Evans, “The nuclear receptor superfamily: a rosetta stone for physiology,” Molecular Endocrinology, vol. 19, no. 6, pp. 1429–1438, 2005.
- N. Mitro, P. A. Mak, L. Vargas, et al., “The nuclear receptor LXR is a glucose sensor,” Nature, vol. 445, no. 7124, pp. 219–223, 2007.
- J. T. Rodgers, C. Lerin, W. Haas, S. P. Gygi, B. M. Spiegelman, and P. Puigserver, “Nutrient control of glucose homeostasis through a complex of PGC-1 and SIRT1,” Nature, vol. 434, no. 7029, pp. 113–118, 2005.
- J. Vanamala, A. Glagolenko, P. Yang, et al., “Dietary fish oil and pectin enhance colonocyte apoptosis in part through suppression of PPAR/ and elevation of ,” Carcinogenesis, vol. 29, no. 4, pp. 790–796, 2008.
- H. Kohno, R. Suzuki, Y. Yasui, M. Hosokawa, K. Miyashita, and T. Tanaka, “Pomegranate seed oil rich in conjugated linolenic acid suppresses chemically induced colon carcinogenesis in rats,” Cancer Science, vol. 95, no. 6, pp. 481–486, 2004.
- H. Kohno, Y. Yasui, R. Suzuki, M. Hosokawa, K. Miyashita, and T. Tanaka, “Dietary seed oil rich in conjugated linolenic acid from bitter melon inhibits azoxymethane-induced rat colon carcinogenesis through elevation of colonic PPAR expression and alteration of lipid composition,” International Journal of Cancer, vol. 110, no. 6, pp. 896–901, 2004.
- B. A. Stoll, “-3 Fatty acids and lipid peroxidation in breast cancer inhibition,” British Journal of Nutrition, vol. 87, no. 3, pp. 193–198, 2002.
- R. E. Teresi, C.-W. Shaiu, C.-S. Chen, V. K. Chatterjee, K. A. Waite, and C. Eng, “Increased PTEN expression due to transcriptional activation of PPAR by lovastatin and rosiglitazone,” International Journal of Cancer, vol. 118, no. 10, pp. 2390–2398, 2006.
- R. Doll, R. Peto, J. Boreham, and I. Sutherland, “Mortality from cancer in relation to smoking: 50 years observations on British doctors,” British Journal of Cancer, vol. 92, no. 3, pp. 426–429, 2005.
- R. Govindarajan, L. Ratnasinghe, D. L. Simmons, et al., “Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes,” Journal of Clinical Oncology, vol. 25, no. 12, pp. 1476–1481, 2007.
- M. Müller and S. Kersten, “Nutrigenomics: goals and strategies,” Nature Reviews Genetics, vol. 4, no. 4, pp. 315–322, 2003.
- L. M. Sanderson, P. J. de Groot, G. J. Hooiveld, et al., “Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics,” PLoS ONE, vol. 3, no. 2, p. e1681, 2008.
- J. M. Zmuda, F. Modugno, J. L. Weissfeld, et al., “Peroxisome proliferator-activated receptor- polymorphism, body mass and prostate cancer risk: evidence for gene-environment interaction,” Oncology, vol. 70, no. 3, pp. 185–189, 2006.
- C. Carlberg and T. W. Dunlop, “An integrated biological approach to nuclear receptor signaling in physiological control and disease,” Critical Reviews in Eukaryotic Gene Expression, vol. 16, no. 1, pp. 1–22, 2006.
- J. J. Hornberg, F. J. Bruggeman, H. V. Westerhoff, and J. Lankelma, “Cancer: a systems biology disease,” Biosystems, vol. 83, no. 2-3, pp. 81–90, 2006.
- M. F. McCarty, “Activation of PPAR may mediate a portion of the anticancer activity of conjugated linoleic acid,” Medical Hypotheses, vol. 55, no. 3, pp. 187–188, 2000.
- M. Armoni, C. Harel, and E. Karnieli, “Transcriptional regulation of the GLUT4 gene: from PPAR- and FOXO1 to FFA and inflammation,” Trends in Endocrinology & Metabolism, vol. 18, no. 3, pp. 100–107, 2007.
- A. V. W. Nunn, J. Bell, and P. Barter, “The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance,” Nuclear Receptor, vol. 5, article 1, 2007.
- O. Warburg, “On the origin of cancer cells,” Science, vol. 123, no. 3191, pp. 309–314, 1956.
- J. M. Cuezva, M. Krajewska, M. L. de Heredia, et al., “The bioenergetic signature of cancer: a marker of tumor progression,” Cancer Research, vol. 62, no. 22, pp. 6674–6681, 2002.
- A. Ramanathan, C. Wang, and S. L. Schreiber, “Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 17, pp. 5992–5997, 2005.
- T. J. Schulz, R. Thierbach, A. Voigt, et al., “Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited,” Journal of Biological Chemistry, vol. 281, no. 2, pp. 977–981, 2006.
- J. A. Tayek, “A review of cancer cachexia and abnormal glucose metabolism in humans with cancer,” Journal of the American College of Nutrition, vol. 11, no. 4, pp. 445–456, 1992.
- J. Bassaganya-Riera, K. Reynolds, S. Martino-Catt, et al., “Activation of PPAR and by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease,” Gastroenterology, vol. 127, no. 3, pp. 777–791, 2004.
- M. B. Sporn, N. Suh, and D. J. Mangelsdorf, “Prospects for prevention and treatment of cancer with selective PPAR modulators (SPARMs),” Trends in Molecular Medicine, vol. 7, no. 9, pp. 395–400, 2001.