Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2008, Article ID 436489, 10 pages
http://dx.doi.org/10.1155/2008/436489
Review Article

PPAR : The Portrait of a Target Ally to Cancer Chemopreventive Agents

1Department of Biological Applications and Technologies, University of Ioannina, Ioannina 45110, Greece
2Institute of Cancer Research, Royal Cancer Hospital, Sutton Surrey, London SM2 5NG, UK
3Department of Medical Oncology, School of Medicine, University of Ioannina, Ioannina 45110, Greece

Received 4 March 2008; Revised 22 May 2008; Accepted 16 July 2008

Academic Editor: Dipak Panigrahy

Copyright © 2008 Ioannis Sainis 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.

Abstract

Peroxisome proliferator-activated receptor-gamma (PPAR ), one of three ligand-activated transcription factors named PPAR, has been identified as a molecular target for cancer chemopreventive agents. PPAR was initially understood as a regulator of adipocyte differentiation and glucose homeostasis while later on, it became evident that it is also involved in cell differentiation, apoptosis, and angiogenesis, biological processes which are deregulated in cancer. It is now established that PPAR ligands can induce cell differentiation and yield early antineoplastic effects in several tumor types. Moreover, several bioactive natural products with cancer protecting potential are shown to operate through activation of PPAR . Overall, PPAR appears to be a prevalent target ally to cancer chemopreventive agents and therefore pursuing research in this area is of great relevance.

1. Introduction

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that function as transcription factors regulating the expression of genes involved in lipid biosynthesis, glucose metabolism, as well as cell proliferation, differentiation, and survival [14]. Their discovery was driven by search of a molecular target for peroxisome proliferators, a group of agents named after their property to increase peroxisomes in rodent liver [5, 6]. Later on, activity studies helped elucidate the versatile role of these molecules in modulating diverse biological functions such as metabolism, tissue remodeling, inflammation, angiogenesis, and carcinogenesis [711]. Three PPAR gene types have been identified: , and γ [12, 13]. Between them, PPARγ is the most intensively investigated [14, 15].

2. The Human PPARγ Gene

The human PPARγ gene consists of six coding exons located at chromosome 3p25.2 and extends approximately over 100 kb of genomic DNA [16]. Three major transcriptional start sites have identified where three mature mRNAs originate from, differing in their untranslated regions [17, 18]. Notably PPARγ1 and PPARγ3 mRNAs code for the same protein of 475 amino acids, while PPARγ2 transcript codes for a different protein which contains an additional 28 N-terminal amino acids [19].

2.1. Tissue Distribution of Different PPARγ Isoforms

The PPARγ1 is found in virtually all tissues, such as liver, skeletal muscle, prostate, kidney, breast, intestine, and the gonads. The PPARγ2 is the major PPARγ isoform expressed mainly in adipose tissue where it normally operates as an adipocyte-specific transcription factor in preadipocytes and regulates adipose tissue differentiation, and the PPARγ3 isoform is restricted to adipose tissue and large intestine [18, 20],

2.2. PPARγ Protein Structure and Function

Similar to other members of the nuclear hormone receptors superfamily, PPARγ protein has three functional domains: the N-terminal domain, the DNA-binding domain, and a carboxy-terminal ligand-binding pocket (Figure 1).

436489.fig.001
Figure 1: Peroxisome proliferator-activated receptor-γ and ligands: pathways and functions. PPARγ protein exhibits a structural organization consisting of three functional domains: an N-terminal domain, a DNA-binding domain (DBD) and a carboxy-terminal ligand binding domain (LBD). PPARγ forms heterodimers with a second member of the nuclear receptor family, the retinoic X receptor (RXR). Unliganded PPARγ suppresses transcription (pathway A) either by interfering with key transcription factors (pathway A1) or through recruitment of corepressors (CoRep) on a PPRE element (pathway A2). Ligand binding to PPARγ (pathway B) triggers conformational changes that lead to dissociation of corepressors (CoRep) and subsequent association of coactivators (CoAct). The complex is binding to PPREs and triggers transcription (pathway B). PPARs ligands can also exert their action through PPARγ-independent mechanisms also (pathway C). For instance in NSCLC cell lines activation of TNF-TRAIL induce apoptosis, while PGE2 degradation, trough 15-hydroxyprostagladin dehydrogenase induction, results in enhanced epithelial differentiation. In endothelial cells PPARγ ligands can markedly boost expression of CD36 which functions as the receptor of endogenous antiangiogenic molecule thrombospondin-1, thereby potentiating the apoptotic response. (PFAs: polyunsaturated fatty acids, TZDs: thiazolidinediones, PPRE: peroxisome proliferator response element, TNF: tumor necrosis factor, TRAIL: TNF-related apoptosis-inducing ligand, NSCLC: non-small cell lung carcinoma).

PPARγ protein receptor is activated by a number of endogenous and exogenous ligands of various potencies. Among pharmaceutical compounds, thiazolidinedione (TZD) class of insulin-sensitizing drugs (also called glitazones) are best known to operate as ligands to PPARγ [21, 22] while long-chain polyunsaturated fatty acids are the most well-characterized endogenous ligands [23].

The activated PPARγ protein becomes operational following its heterodimerization with retinoid X receptors (RXR) [24]. The PPARγ/RXR complex translocates to the nucleus where it binds to target genes which contain a peroxisome proliferator response element (PPRE). A PPRE consist of a direct repetition of the consensus sequence AGGTCA separated by a single nucleotide (Direct repetition; DR1) [17]. To initiate transcriptional regulation of PPRE-bearing genes, the PPARγ/RXR complex requires accessory proteins to bind on. These proteins can either trigger (coactivators) or represses gene transcription (corepressors) (Figure 1). It must be noted though that besides their PPARγ-dependent genomic effects, PPARγ ligands can also influence cellular biology via nongenomic, PPARγ-independent events [25] (Figure 1).

As a rule, the transcriptional activity of PPARγ is negatively modulated through phosphorylation by MAPK [2628]. Phosphorylation of human PPARγ1 protein at Ser-84 site restrains its function [27], and phosphorylation of PPARγ2 modifies the A/B domain and reduces its ligand binding affinity [29]. However, not all phosphorylation events are inhibitory. For example, it has been found that missense mutation which results in the conversion of proline to glutamine at position 115 can render PPARγ2 constitutively active through modulation of the MAPK-dependent phosphorylation status of serine 114 [30] while phosphorylation by protein kinase A (PKA) was shown to enhance its activity [31].

Until now, three molecular processes have been proposed for the termination and downregulation of PPARγ signaling: the phosphorylation of Ser-84/112 of PPARγ1/2 by ERKs [27], the proteasomal degradation of ligand-activated PPARγ [32], and the interaction with MEKs, which promotes its expulsion from the nucleus [33].

3. PPARγ in Cancer

Early studies portrayed PPARγ as an important regulator of preadipocyte differentiation and glucose homeostasis. Later on, it was identified that PPARγ regulates biological processes which are considered hallmarks of cancer such as cell differentiation, apoptosis, and angiogenesis. This knowledge, coupled with data showing that PPARγ ligands could yield anticancer effects in several cell types, led researches postulate a role for PPARγ in carcinogenesis [11, 34, 35].

Apoptosis is believed to be a fundamental molecular mechanism through which PPARγ activators exert their action against cells which undergo malignant transformation [3638]. Moreover, apart from their direct inhibitory effects on cancerous transformed cells, PPARγ can also inhibit angiogenesis which is a prerequisite for tumor formation and growth [3941]. It is suggested that the antiangiogenic activity of PPARγ can be accomplished either by blocking the production the angiogenic ELR+CXC chemokines by cancer transformed cells or by inducing expression of the thrombospondin-1 receptor CD36 in endothelial cells [4244] In addition, latest exciting data, which showed that PPARγ agonists were able to inhibit the canonical WNT signaling in human colonic epithelium, raises hopes that such agents can possibly block cancer initiation at a stem cell level [45].

It must be underlined herein that despite demonstration of cancer-preventive effects of PPARγ ligands in vitro, clinical trials and animal models failed so far to show significant benefits [46]. The fact that PPARγ ligands have been used in clinic trials at concentrations above those needed to elicit receptor agonistic activity poses questions for receptor-independent off-target effects [47].

3.1. PPARγ and Gastrointestinal Cancer

PPARγ are heterogeneously expressed throughout the gastrointestinal epithelium, showing significant differences in abundance, distribution, and functions. This protein is principally expressed in differentiated epithelial colonic cells, preferably in the proximal colon [48]. Sarraf et al. showed that PPARγ activation could stimulate a program that is characteristic of colonic cell differentiation [49].

A functional genomics analysis conducted for the identification of PPARγ gene targets revealed that the majority of these genes were transcribed throughout the colon, but their expression varied in cells purified from the proximal colon and in those from the distal colon. Metabolic functions of PPARγ were elicited primarily in the proximal colon, whereas signaling functions were recognized in the distal colon. Interestingly, TZDs transactivated the PPARγ gene targets at the proximal colon but repressed them in the distal colon. TSC22, a TGFβ target gene known to inhibit colon cell proliferation, was also identified as a PPARγ target gene [50]. It is worth mentioning that both TGFβ and PPARγ pathways attenuate during transition from adenoma to carcinoma [51]. From a pharmacological point of view, Yamazaki at al. showed that activation of the RXR/PPARγ heterodimer by their respective ligands could be considered a useful chemopreventive strategy for colorectal cancer. They found that a combination of the RXR alpha ligand 9-cis-retinoic acid with ciglitazone synergistically inhibited the cell growth and induced apoptosis in Caco2 human colon cancer cells that expressed high levels of p-RXR alpha protein [52].

In the most widely used preclinical model of sporadic colon carcinogenesis, the azoxymethane-treated mice, activation of PPARγ suppressed carcinogenesis but only before damage to the APC/beta-catenin pathway [53]. However, two papers published ten years ago reported that troglitazone and rosiglitazone increased occurrence of colon tumors in mice-caring mutations in the APC gene [48, 54]. Moreover, although pioglitazone was later reported to suppresses colon tumor growth in Apc+/− mice [55], biallelic knockdown of PPARγ in colonic epithelial cells was associated with an increase of tumor incidence [56]. It should be reminded, however, that although TZDs are considered pure PPAR agonists, they also wield off-target effects not mediated through linkage to PPAR receptors. An in-depth analysis of the role of TZDs against colon cancer can be facilitated through development of tissue-specific PPARγ knockout mice [57]. Interestingly, a small phase II clinical trial using troglitazone failed to document tumor responses in patients with advance stage metastatic colon cancer [58].

Overall, existing evidence indicates that PPARγ agonists have a potential to inhibit cancer formation in the distal colon, but they are practically inactive in advanced stages of colon cancer.

3.2. PPARγ and lung Cancer

Lung cancer is a major global health problem because of its incidence and mortality. It remains the top cancer killer worldwide to which early-detection strategies and development of new therapies failed so far to improve its lethal outcome [59]. This tobacco-related cancer epidemic persists despite public implementation of tobacco control measures because the majority of tobacco-smoke users declare powerlessness to quit. Therefore, the search for potent chemopreventive agents and the development of effective chemoprevention strategies for lung cancer is a viable pursuit highly justified [60, 61].

Several studies have shown that PPARγ agonists can inhibit growth and induce changes associated with differentiation and apoptosis in lung cancer [6264]. TZDs induced upregulation of PTEN and p21, downregulation of cyclins D and E, and reduced expression of fibronectin and its receptor integrin α5β1 in human lung carcinoma cell lines [6568].

A first evidence of clinical efficacy of PPARγ agonists as cancer chemopreventives in lung cancer was recently published. A retrospective analysis of a database from ten Veteran Affairs medical centers revealed a significant reduction (33%) in lung cancer risk in diabetic patients who were treated with TZDs compared with nonusers of TZDs [69]. However, other studies damped early this enthusiasm by showing that diabetic patients treated with TZDs were at increased risk for cardiovascular complications [70].

It is critical to understand that cancer-protecting effects of PPARγ agonists in lung cancer can be PPARγ dependent but also PPARγ independent [71]. Characteristically, TZDs suppressed the expression of antiapoptotic mediator prostaglandin E(2) in NCLC cells through induction of 15-hydroxyprostagladin dehydrogenase [72] and enhanced TRAIL-induced apoptosis through upregulation of death receptor 5 DR5 and downregulation of c-FLIP in human lung cancer cells [73].

The combination of PPARγ agonists with other chemopreventive agents emerges as a challenging issue in lung cancer chemoprophylaxis. Notably, an amazing synergy of clinically achievable concentrations of lovastatin (an HMG-CoA reductase inhibitor) and troglitazone was recently shown against lung cancer cells [74]. This effect was accompanied by synergistic modulation of E2F-1, p27 Kip1, CDK2, cyclin A and RB. In another study, a combination of low-doses of MK886 (5-lipoxygenase activating protein-directed inhibitor), ciglitazone and 13-cis-retinoic acid, also demonstrated synergistic inhibitory activity against lung cancer cells [75]. These studies provide a framework for the development of rationally designed drug combinations aimed to target simultaneously the PPARγ and other cofactors.

3.3. PPARγ and other Malignancies

Epidemiological studies suggested that high consumption of carotenoids (known PPARγ activators) could protect women from the development of breast cancer [76, 77]. These findings are also supported by experiments which show that activation of PPARγ can induce terminal differentiation, cell cycle arrest, or apoptosis of preneoplastic and cancerous mammary epithelial cells [7880]. Unfortunately, this is not the case for advanced breast cancer: a phase II trial of troglitazone in patients with breast cancer metastases failed recently to prove clinical benefits [81].

Prostate cancer appears to be an attractive tumor target for PPARγ agonists because cancerous prostate cells express higher levels of PPARγ compared with their normal counterparts [82]. Moreover, it has been shown that PPARγ1/2 activation suppressed the high level of endogenous COX-2 in normal prostate epithelial cells [83] while TZDs mediated apoptosis in prostate cancer cells through inhibition of Bcl-xL/Bcl-2 functions [84]. In the clinical setting, reduction and prolonged stabilization of prostate-specific antigen levels were demonstrated in patients treated with troglitazone [82, 85]. The above data provide a rationale to consider investigating PPARγ ligands for their role in preventive and possibly therapeutic management of prostate cancer.

In gynecological cancer, Wu et al. reported that rosiglitazone could block or delay the development of hyperplasia and subsequent endometrial cancer. This PPARγ agonist induced apoptosis in both PTEN intact and PTEN null cancer cell lines and decreased proliferation of the endometrial hyperplastic lesions in a PTEN(+/−) murine model [86].

In human pancreatic cancer cell lines, treatment with TZDs was found to induce cell cycle arrest and increase expression of pancreatic differentiation markers [87, 88]. Moreover, activation of PPARγ together with RXR resulted in suppression of pancreatic cancer cell growth through suppression of cyclin D1 [89].

Among sarcoma tumors, it is liposarcomas which are considered targets for PPARγ agonists because they show a high expression of this nuclear receptor [90]. However, although pioglitazone was found capable to terminally differentiate human liposarcoma cells in vitro, it failed an early phase II trial despite induced changes in relevant target genes [91].

In thyroid cancer, a functional chromosomal translocation of part of PAX8 gene which encodes the DNA-binding domain to the activation domain of the PPARγ gene has been detected in patients with follicular type carcinoma [92]. This chimeric fusion protein is resistant to PPARγ ligands, invalidating any anticancer effects of PPARγ ligands in this setting. However, it has been suggested that PPARγ ligands could have activity in combination with retinoids and/or histone deacetylase inhibitors in thyroid tumors which express both PPARγ and also RXRγ [93, 94].

4. PPARγ as a Mediator to Cancer Protecting Natural Products

Evidence has accumulated which affirms that bioactive natural compounds can play an important role in cancer chemoprevention through modulation of PPARγ. Preclinical studies and epidemiological data support that tumor growth and metastasis can be restrained or delayed by several herbal products [9598]. Moreover, it is believed that novel agents derived from bioactive phytochemicals can be used as adjuncts to enhance therapeutic efficacy of standard treatments [99, 100]. Among natural products, triterpenoids, flavononoids, carotenoids, and linoleic acid are the most extensively studied as cancer chemopreventives and have invariably been found to operate as PPARγ activators.

Terpenoids of plant origin have shown antitumor activity which indicates a potential role for these compounds as cancer chemopreventives [100102]. Specifically, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a synthetic triterpenoid, which was shown to activate PPARγ and induce growth arrest and apoptosis in treated breast cancer cells [103]; also, glycyrrhizin the major triterpene gycoside phytochemical in licorice root and the triterpenoid acid betulinic acid which is found in the bark of several species of plants, both have shown pro-PPARγ activities in cancer cells. These phytochemicals were found to induce expression of proapoptotic protein caveolin-1 and the tumor-suppressor gene Kruppel-like factor-4 (KLF-4) in colon and pancreatic cancer cells [104, 105]. It should though be noted that although caveolin-1 is generally considered a proapoptotic molecule, it has also been associated with drug resistance and possibly metastasis [106]. It is believed that some PPAR-γ agonists induce whilst others repress caveolin-1 [107].

Isoflavones are well known to function as phytoestrogens. They bind to the estrogen-related receptors but also to PPARα and PPARγ [108]. As a result, their biological effects are determined by the balance between activated ERs and PPARγ [109]. Liang et al. investigated apigenin, chrysin, and kaempferol in mouse macrophages and found that these flavonoids stimulated PPARγ transcriptional activities as allosteric effectors rather than pure agonists [110]. In the clinical setting, purified isoflavones have only been investigated for safety, bioavailability, and pharmacokinetics in men with early-stage prostate cancer [111114].

Carotenoids are another class of phytochemicals found to activate PPARγ in cancer cells. Hosokawa et al. reported that the edible carotenoid fucoxanthin, when combined with troglitazone, induced apoptosis of Caco-2 cells [115]. Moreover, in epidemiological studies, consumption of carotenoids was shown to protect against breast cancer [76, 77]. Interestingly, Cui et al. unveiled recently the molecular mechanisms which underlie the chemopreventive activity of β-carotene against breast cancer. They found that β-carotene significantly increased PPARγ mRNA and protein levels in a time-dependent fashion, while 2-chloro-5-nitro-N-phenylbenzamide (GW9662), an irreversible PPARγ antagonist, attenuated apoptosis caused by β-carotene in cancer-transformed cells [36].

Linoleic acid, a naturally occurring omega-6 fatty acid which is abundant in many vegetable oils, has been studied comprehensively for its prophylactic effects against cancer formation [116]. Conjugated linoleic acid, which is found especially in eggs and in the meat and dairy products of grass-fed ruminants, was shown to modulate cell-cell adhesion and invasiveness of MCF-7 cells through regulation of PPARγ expression [117]. Moreover α-eleostearic acid (ESA), a linolenic acid isomer, induced apoptosis in endothelial cells and inhibited angiogenesis, also through activation of PPARγ [118]. More recent studies brought up additional evidence and provided insights into molecular mechanisms of the protective effects of linoleic acid against colon cancer. Yasui et al. reported that 9trans-11trans-conjugated linoleic acid inhibited the development of azoxymethane-induced colonic aberrant crypt foci in rats at preinitiation and postinitiation level through activation of PPARγ and downregulation of cyclooxygenase-2 and cyclin D1 [119]. In addition, Sasaki at al. showed that linoleic acid was capable to inhibit azoxymethane-induced transformation of intestinal cells and tumor formation [120]. In most studies, the differentiation-promoting and carcinogenesis-blocking effects were mostly attributed to activation of PPARγ by linoleic acid products [121]. Finally, apart from its direct action as a PPARγ activator, linoleic acid was found to modulate interactions between PPARβ/δ and PPARγ isoforms [122].

Finally, in the class of capsaicinoids, capsaicin, the spicy component of hot peppers, was shown to induce apoptosis of melanoma as well as colon and prostate cancer cells, and was associated with activation of the PPARγ in the case of colon cancer [123125]. However, controversy exists regarding cancer-preventing and cancer-promoting effects of capsaicin [126, 127].

It must be noted that besides their PPARγ-mediated effects, natural products can also induce transcription of detoxification enzymes glutathione S-transferases (GST) which are known to protect cells from chemical-induced carcinogenesis [128, 129]. Recently, Park et al. examined GSTA2 gene induction by thiazolidinedione and 9-cis-retinoic acid and investigated the molecular basis of PPARγ/RXR-mediated GSTA2 induction in the H4IIE hepatocytes. They found that both PPARγ and RXR agonists could increase the expression of GSTA2 but treatment of cells with a combination of PPARγ and RXR agonists produced synergistic increase [130]. This data suggest that cancer-preventive functions of PPARγ activators may be related to some extent to a parallel induction of GSTA2.

5. Conclusion

Existing data suggest that peroxisome proliferator-activated receptor-gamma (PPARγ) is a potential target ally to cancer chemopreventive agents. Although PPARγ was first understood as a key regulator of adipocyte differentiation and glucose homeostasis, it is now recognized that it is also involved in cell proliferation, differentiation, apoptosis, and angiogenesis. Meticulous research for PPARγ agonists with potency to function as cancer chemopreventive agents is highly warranted.

References

  1. J. N. Feige, L. Gelman, L. Michalik, B. Desvergne, and W. Wahli, “From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions,” Progress in Lipid Research, vol. 45, no. 2, pp. 120–159, 2006. View at Publisher · View at Google Scholar · View at PubMed
  2. C. Dreyer, G. Krey, H. Keller, F. Givel, G. Helftenbein, and W. Wahli, “Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors,” Cell, vol. 68, no. 5, pp. 879–887, 1992. View at Publisher · View at Google Scholar
  3. B. Desvergne and W. Wahli, “Peroxisome proliferator-activated receptors: nuclear control of metabolism,” Endocrine Reviews, vol. 20, no. 5, pp. 649–688, 1999. View at Publisher · View at Google Scholar
  4. A. Chawta, J. J. Repa, R. M. Evans, and D. J. Mangelsdorf, “Nuclear receptors and lipid physiology: opening the X-files,” Science, vol. 294, no. 5548, pp. 1866–1870, 2001. View at Publisher · View at Google Scholar · View at PubMed
  5. I. Issemann and S. Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,” Nature, vol. 347, no. 6294, pp. 645–650, 1990. View at Publisher · View at Google Scholar · View at PubMed
  6. E. A. Lock, A. M. Mitchell, and C. R. Elcombe, “Biochemical mechanisms of induction of hepatic peroxisome proliferation,” Annual Review of Pharmacology and Toxicology, vol. 29, pp. 145–163, 1989. View at Publisher · View at Google Scholar · View at PubMed
  7. S. Kersten, B. Desvergne, and W. Wahli, “Roles of PPARS in health and disease,” Nature, vol. 405, no. 6785, pp. 421–424, 2000. View at Publisher · View at Google Scholar · View at PubMed
  8. J. C. Corton, S. P. Anderson, and A. Stauber, “Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators,” Annual Review of Pharmacology and Toxicology, vol. 40, pp. 491–518, 2000. View at Publisher · View at Google Scholar · View at PubMed
  9. D. Panigrahy, S. Singer, L. Q. Shen et al., “PPARγ ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis,” The Journal of Clinical Investigation, vol. 110, no. 7, pp. 923–932, 2002. View at Publisher · View at Google Scholar
  10. C. J. Nicol, M. Yoon, J. M. Ward et al., “PPARγ influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis,” Carcinogenesis, vol. 25, no. 9, pp. 1747–1755, 2004. View at Publisher · View at Google Scholar · View at PubMed
  11. G. Martinasso, M. Oraldi, A. Trombetta et al., “Involvement of PPARs in cell proliferation and apoptosis in human colon cancer specimens and in normal and cancer cell lines,” PPAR Research, vol. 2007, Article ID 93416, 9 pages, 2007. View at Publisher · View at Google Scholar · View at PubMed
  12. R. Hertz and J. Bar-Tana, “Peroxisome proliferator-activated receptor (PPAR) alpha activation and its consequences in humans,” Toxicology Letters, vol. 102-103, pp. 85–90, 1998. View at Publisher · View at Google Scholar
  13. L. K. Larsen, E.-Z. Amri, S. Mandrup, C. Pacot, and K. Kristiansen, “Genomic organization of the mouse peroxisome proliferator-activated receptor β/δ gene: alternative promoter usage and splicing yield transcripts exhibiting differential translational efficiency,” Biochemical Journal, vol. 366, no. 3, pp. 767–775, 2002. View at Publisher · View at Google Scholar · View at PubMed
  14. J. Berger and D. E. Moller, “The mechanisms of action of PPARs,” Annual Review of Medicine, vol. 53, pp. 409–435, 2002. View at Publisher · View at Google Scholar · View at PubMed
  15. M. Lehrke and M. A. Lazar, “The many faces of PPARγ,” Cell, vol. 123, no. 6, pp. 993–999, 2005. View at Publisher · View at Google Scholar · View at PubMed
  16. B. A. Beamer, C. Negri, C.-J. Yen et al., “Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma (hPPARγ) gene,” Biochemical and Biophysical Research Communications, vol. 233, no. 3, pp. 756–759, 1997. View at Publisher · View at Google Scholar · View at PubMed
  17. L. Fajas, D. Auboeuf, E. Raspé et al., “The organization, promoter analysis, and expression of the human PPARγ gene,” The Journal of Biological Chemistry, vol. 272, no. 30, pp. 18779–18789, 1997. View at Publisher · View at Google Scholar
  18. L. Fajas, J.-C. Fruchart, and J. Auwerx, “PPARγ3 mRNA: a distinct PPARγ mRNA subtype transcribed from an independent promoter,” FEBS Letters, vol. 438, no. 1-2, pp. 55–60, 1998. View at Publisher · View at Google Scholar
  19. P. Tontonoz, E. Hu, R. A. Graves, A. I. Budavari, and B. M. Spiegelman, “mPPARγ2: tissue-specific regulator of an adipocyte enhancer,” Genes & Development, vol. 8, no. 10, pp. 1224–1234, 1994. View at Publisher · View at Google Scholar
  20. R. Mukherjee, L. Jow, G. E. Croston, and J. R. Paterniti, Jr., “Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARγ2 versus PPARγ1 and activation with retinoid X receptor agonists and antagonists,” The Journal of Biological Chemistry, vol. 272, no. 12, pp. 8071–8076, 1997. View at Publisher · View at Google Scholar
  21. R. T. Nolte, G. B. Wisely, S. Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator- activated receptor-γ,” Nature, vol. 395, no. 6698, pp. 137–143, 1998. View at Publisher · View at Google Scholar · View at PubMed
  22. J. Uppenberg, C. Svensson, M. Jaki, G. Bertilsson, L. Jendeberg, and A. Berkenstam, “Crystal structure of the ligand binding domain of the human nuclear receptor PPARγ,” The Journal of Biological Chemistry, vol. 273, no. 47, pp. 31108–31112, 1998. View at Publisher · View at Google Scholar
  23. I. Issemann, R. A. Prince, J. D. Tugwood, and S. Green, “The peroxisome proliferator-activated receptor: retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs,” The Journal of Molecular Endocrinology, vol. 11, no. 1, pp. 37–47, 1993. View at Google Scholar
  24. S. A. Kliewer, K. Umesono, D. J. Noonan, R. A. Heyman, and R. M. Evans, “Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors,” Nature, vol. 358, no. 6389, pp. 771–774, 1992. View at Publisher · View at Google Scholar · View at PubMed
  25. E. Burgermeister and R. Seger, “MAPK kinases as nucleo-cytoplasmic shuttles for PPARγ,” Cell Cycle, vol. 6, no. 13, pp. 1539–1548, 2007. View at Google Scholar
  26. E. Hu, J. B. Kim, P. Sarraf, and B. M. Spiegelman, “Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARγ,” Science, vol. 274, no. 5295, pp. 2100–2103, 1996. View at Publisher · View at Google Scholar
  27. M. Adams, M. J. Reginato, D. Shao, M. A. Lazar, and V. K. Chatterjee, “Transcriptional activation by peroxisome proliferator-activated receptor γ is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site,” The Journal of Biological Chemistry, vol. 272, no. 8, pp. 5128–5132, 1997. View at Publisher · View at Google Scholar
  28. K. A. Burns and J. P. Vanden Heuvel, “Modulation of PPAR activity via phosphorylation,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 952–960, 2007. View at Publisher · View at Google Scholar · View at PubMed
  29. D. Shao, S. M. Rangwala, S. T. Bailey, S. L. Krakow, M. J. Reginato, and M. A. Lazar, “Interdomain communication regulating ligand binding by PPAR-γ,” Nature, vol. 396, no. 6709, pp. 377–380, 1998. View at Publisher · View at Google Scholar · View at PubMed
  30. M. Ristow, D. Müller-Wieland, A. Pfeiffer, W. Krone, and C. R. Kahn, “Obesity associated with a mutation in a genetic regulator of adipocyte differentiation,” The New England Journal of Medicine, vol. 339, no. 14, pp. 953–959, 1998. View at Publisher · View at Google Scholar
  31. G. Lazennec, L. Canaple, D. Saugy, and W. Wahli, “Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators,” Molecular Endocrinology, vol. 14, no. 12, pp. 1962–1975, 2000. View at Publisher · View at Google Scholar
  32. Z. E. Floyd and J. M. Stephens, “Interferon-γ-mediated activation and ubiquitin-proteasome-dependent degradation of PPARγ in adipocytes,” The Journal of Biological Chemistry, vol. 277, no. 6, pp. 4062–4068, 2002. View at Publisher · View at Google Scholar · View at PubMed
  33. 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 γ,” Molecular and Cellular Biology, vol. 27, no. 3, pp. 803–817, 2007. View at Publisher · View at Google Scholar · View at PubMed
  34. L. Michalik, B. Desvergne, and W. Wahli, “Peroxisome-proliferator-activated receptors and cancers: complex stories,” Nature Reviews Cancer, vol. 4, no. 1, pp. 61–70, 2004. View at Publisher · View at Google Scholar · View at PubMed
  35. C. Grommes, G. E. Landreth, M. Sastre et al., “Inhibition of in vivo glioma growth and invasion by peroxisome proliferator-activated receptor γ agonist treatment,” Molecular Pharmacology, vol. 70, no. 5, pp. 1524–1533, 2006. View at Publisher · View at Google Scholar · View at PubMed
  36. Y. Cui, Z. Lu, L. Bai, Z. Shi, W.-E. Zhao, and B. Zhao, “β-carotene induces apoptosis and up-regulates peroxisome proliferator-activated receptor γ expression and reactive oxygen species production in MCF-7 cancer cells,” European Journal of Cancer, vol. 43, no. 17, pp. 2590–2601, 2007. View at Publisher · View at Google Scholar · View at PubMed
  37. H. Sun, I. M. Berquin, R. T. Owens, J. T. O'Flaherty, and I. J. Edwards, “Peroxisome proliferator-activated receptor β-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells,” Cancer Research, vol. 68, no. 8, pp. 2912–2919, 2008. View at Publisher · View at Google Scholar · View at PubMed
  38. I. Borbath, I. Leclercq, P. Moulin, C. Sempoux, and Y. Horsmans, “The PPARgamma agonist pioglitazone inhibits early neoplastic occurrence in the rat liver,” European Journal of Cancer, vol. 43, no. 11, pp. 1755–1763, 2007. View at Publisher · View at Google Scholar · View at PubMed
  39. J. Folkman, “Angiogenesis: an organizing principle for drug discovery?,” Nature Reviews Drug Discovery, vol. 6, no. 4, pp. 273–286, 2007. View at Publisher · View at Google Scholar · View at PubMed
  40. C. Giaginis, A. Tsantili-Kakoulidou, and S. Theocharis, “Peroxisome proliferator-activated receptor-γ ligands: potential pharmacological agents for targeting the angiogenesis signaling cascade in cancer,” PPAR Research, vol. 2008, Article ID 431763, 12 pages, 2008. View at Publisher · View at Google Scholar · View at PubMed
  41. D. Panigrahy, S. Huang, M. W. Kieran, and A. Kaipainen, “PPARγ as a therapeutic target for tumor angiogenesis and metastasis,” Cancer Biology and Therapy, vol. 4, no. 7, pp. 687–693, 2005. View at Google Scholar
  42. V. G. Keshamouni, D. A. Arenberg, R. C. Reddy, M. J. Newstead, S. Anthwal, and T. J. Standiford, “PPAR-γ activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer,” Neoplasia, vol. 7, no. 3, pp. 294–301, 2005. View at Publisher · View at Google Scholar · View at PubMed
  43. H. Huang, S. C. Campbell, D. F. Bedford et al., “Peroxisome proliferator-activated receptor γ ligands improve the antitumor efficacy of thrombospondin peptide ABT510,” Molecular Cancer Research, vol. 2, no. 10, pp. 541–550, 2004. View at Google Scholar
  44. M. F. McCarty, J. Barroso-Aranda, and F. Contreras, “PPARgamma agonists can be expected to potentiate the efficacy of metronomic chemotherapy through CD36 up-regulation,” Medical Hypotheses, vol. 70, no. 2, pp. 419–423, 2008. View at Publisher · View at Google Scholar · View at PubMed
  45. M. Katoh and M. Katoh, “WNT signaling pathway and stem cell signaling network,” Clinical Cancer Research, vol. 13, no. 14, pp. 4042–4045, 2007. View at Publisher · View at Google Scholar · View at PubMed
  46. A. Galli, T. Mello, E. Ceni, E. Surrenti, and C. Surrenti, “The potential of antidiabetic thiazolidinediones for anticancer therapy,” Expert Opinion on Investigational Drugs, vol. 15, no. 9, pp. 1039–1049, 2006. View at Publisher · View at Google Scholar · View at PubMed
  47. L. D. Yee, N. Williams, P. Wen et al., “Pilot study of rosiglitazone therapy in women with breast cancer: effects of short-term therapy on tumor tissue and serum markers,” Clinical Cancer Research, vol. 13, no. 1, pp. 246–252, 2007. View at Publisher · View at Google Scholar · View at PubMed
  48. A.-M. Lefebvre, B. Paulweber, L. Fajas et al., “Peroxisome proliferator-activated receptor gamma is induced during differentiation of colon epithelium cells,” Journal of Endocrinology, vol. 162, no. 3, pp. 331–340, 1999. View at Publisher · View at Google Scholar
  49. P. Sarraf, E. Mueller, D. Jones et al., “Differentiation and reversal of malignant changes in colon cancer through PPARγ,” Nature Medicine, vol. 4, no. 9, pp. 1046–1052, 1998. View at Publisher · View at Google Scholar · View at PubMed
  50. R. A. Gupta, P. Sarraf, J. A. Brockman et al., “Peroxisome proliferator-activated receptor γ and transforming growth factor-β pathways inhibit intestinal epithelial cell growth by regulating levels of TSC-22,” The Journal of Biological Chemistry, vol. 278, no. 9, pp. 7431–7438, 2003. View at Publisher · View at Google Scholar · View at PubMed
  51. A. J. Chang, D. H. Song, and M. M. Wolfe, “Attenuation of peroxisome proliferator-activated receptor γ (PPARγ) mediates gastrin-stimulated colorectal cancer cell proliferation,” The Journal of Biological Chemistry, vol. 281, no. 21, pp. 14700–14710, 2006. View at Publisher · View at Google Scholar · View at PubMed
  52. K. Yamazaki, M. Shimizu, M. Okuno et al., “Synergistic effects of RXRα and PPARγ ligands to inhibit growth in human colon cancer cells—phosphorylated RXRα is a critical target for colon cancer management,” Gut, vol. 56, no. 11, pp. 1557–1563, 2007. View at Publisher · View at Google Scholar · View at PubMed
  53. G. D. Girnun, W. M. Smith, S. Drori et al., “APC-dependent suppression of colon carcinogenesis by PPARγ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 21, pp. 13771–13776, 2002. View at Publisher · View at Google Scholar · View at PubMed
  54. E. Saez, P. Tontonoz, M. C. Nelson et al., “Activators of the nuclear receptor PPARγ enhance colon polyp formation,” Nature Medicine, vol. 4, no. 9, pp. 1058–1061, 1998. View at Publisher · View at Google Scholar · View at PubMed
  55. N. Niho, M. Takahashi, Y. Shoji et al., “Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARγ ligand,” Cancer Science, vol. 94, no. 11, pp. 960–964, 2003. View at Publisher · View at Google Scholar
  56. C. A. McAlpine, Y. Barak, I. Matise, and R. T. Cormier, “Intestinal-specific PPARγ deficiency enhances tumorigenesis in ApcMin/+ mice,” International Journal of Cancer, vol. 119, no. 10, pp. 2339–2346, 2006. View at Publisher · View at Google Scholar · View at PubMed
  57. E. A. Thompson, “PPARγ physiology and pathology in gastrointestinal epithelial cells,” Molecules and Cells, vol. 24, no. 2, pp. 167–176, 2007. View at Google Scholar
  58. M. H. Kulke, G. D. Demetri, N. E. Sharpless et al., “A phase II study of troglitazone, an activator of the PPARγ receptor, in patients with chemotherapy-resistant metastatic colorectal cancer,” Cancer Journal, vol. 8, no. 5, pp. 395–399, 2002. View at Publisher · View at Google Scholar
  59. P. B. Bach, G. A. Silvestri, M. Hanger, and J. R. Jett, “Screening for lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition),” Chest, vol. 132, no. 3, supplement, pp. 69S–77S, 2007. View at Publisher · View at Google Scholar · View at PubMed
  60. J.-C. Soria, E. S. Kim, J. Fayette, S. Lantuejoul, E. Deutsch, and W. K. Hong, “Chemoprevention of lung cancer,” The Lancet Oncology, vol. 4, no. 11, pp. 659–669, 2003. View at Publisher · View at Google Scholar
  61. F. R. Hirsch and S. M. Lippman, “Advances in the biology of lung cancer chemoprevention,” Journal of Clinical Oncology, vol. 23, no. 14, pp. 3186–3197, 2005. View at Publisher · View at Google Scholar · View at PubMed
  62. T.-H. Chang and E. Szabo, “Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor γ in non-small cell lung cancer,” Cancer Research, vol. 60, no. 4, pp. 1129–1138, 2000. View at Google Scholar
  63. Y. Tsubouchi, H. Sano, Y. Kawahito et al., “Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-γ agonists through induction of apoptosis,” Biochemical and Biophysical Research Communications, vol. 270, no. 2, pp. 400–405, 2000. View at Publisher · View at Google Scholar · View at PubMed
  64. M. Wick, G. Hurteau, C. Dessev et al., “Peroxisome proliferator-activated receptor-γ is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth,” Molecular Pharmacology, vol. 62, no. 5, pp. 1207–1214, 2002. View at Publisher · View at Google Scholar
  65. S. Y. Lee, G. Y. Hur, K. H. Jung et al., “PPAR-γ agonist increase gefitinib's antitumor activity through PTEN expression,” Lung Cancer, vol. 51, no. 3, pp. 297–301, 2006. View at Publisher · View at Google Scholar · View at PubMed
  66. S. Han, N. Sidell, P. B. Fisher, and J. Roman, “Up-regulation of p21 gene expression by peroxisome proliferator-activated receptor γ in human lung carcinoma cells,” Clinical Cancer Research, vol. 10, no. 6, pp. 1911–1919, 2004. View at Publisher · View at Google Scholar
  67. V. G. Keshamouni, R. C. Reddy, D. A. Arenberg et al., “Peroxisome proliferator-activated receptor-γ activation inhibits tumor progression in non-small-cell lung cancer,” Oncogene, vol. 23, no. 1, pp. 100–108, 2004. View at Publisher · View at Google Scholar · View at PubMed
  68. S. Han, H. N. Rivera, and J. Roman, “Peroxisome proliferator-activated receptor-γ ligands inhibit α5 integrin gene transcription in non-small cell lung carcinoma cells,” American Journal of Respiratory Cell and Molecular Biology, vol. 32, no. 4, pp. 350–359, 2005. View at Publisher · View at Google Scholar · View at PubMed
  69. 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. View at Publisher · View at Google Scholar · View at PubMed
  70. S. E. Nissen and K. Wolski, “Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes,” The New England Journal of Medicine, vol. 356, no. 24, pp. 2457–2471, 2007. View at Publisher · View at Google Scholar · View at PubMed
  71. R. A. Nemenoff, “Peroxisome proliferator-activated receptor-γ in lung cancer: defining specific versus “off-target” effectors,” Journal of Thoracic Oncology, vol. 2, no. 11, pp. 989–992, 2007. View at Publisher · View at Google Scholar · View at PubMed
  72. S. Hazra, R. K. Batra, H. H. Tai, S. Sharma, X. Cui, and S. M. Dubinett, “Pioglitazone and rosiglitazone decrease prostaglandin E2 in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin dehydrogenase,” Molecular Pharmacology, vol. 71, no. 6, pp. 1715–1720, 2007. View at Publisher · View at Google Scholar · View at PubMed
  73. W. Zou, X. Liu, P. Yue, F. R. Khuri, and S.-Y. Sun, “PPARγ ligands enhance TRAIL-induced apoptosis through DR5 upregulation and c-FLIP downregulation in human lung cancer cells,” Cancer Biology and Therapy, vol. 6, no. 1, pp. 99–106, 2007. View at Google Scholar
  74. C.-J. Yao, G.-M. Lai, C.-F. Chan, A.-L. Cheng, Y.-Y. Yang, and S.-E. Chuang, “Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone,” International Journal of Cancer, vol. 118, no. 3, pp. 773–779, 2006. View at Publisher · View at Google Scholar · View at PubMed
  75. I. Avis, A. Martínez, J. Tauler et al., “Inhibitors of the arachidonic acid pathway and peroxisome proliferator-activated receptor ligands have superadditive effects on lung cancer growth inhibition,” Cancer Research, vol. 65, no. 10, pp. 4181–4190, 2005. View at Publisher · View at Google Scholar · View at PubMed
  76. J. F. Dorgan, A. Sowell, C. A. Swanson et al., “Relationships of serum carotenoids, retinol, α-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States),” Cancer Causes & Control, vol. 9, no. 1, pp. 89–97, 1998. View at Publisher · View at Google Scholar
  77. P. Toniolo, A. L. Van Kappel, A. Akhmedkhanov et al., “Serum carotenoids and breast cancer,” American Journal of Epidemiology, vol. 153, no. 12, pp. 1142–1147, 2001. View at Publisher · View at Google Scholar
  78. E. Mueller, P. Sarraf, P. Tontonoz et al., “Terminal differentiation of human breast cancer through PPARγ,” Molecular Cell, vol. 1, no. 3, pp. 465–470, 1998. View at Publisher · View at Google Scholar
  79. R. G. Mehta, E. Williamson, M. K. Patel, and H. P. Koeffler, “A ligand of peroxisome proliferator-activated receptor γ, retinoids, and prevention of preneoplastic mammary lesions,” Journal of the National Cancer Institute, vol. 92, no. 5, pp. 418–423, 2000. View at Publisher · View at Google Scholar
  80. E. Elstner, C. Müller, K. Koshizuka et al., “Ligands for peroxisome proliferator-activated receptory 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. View at Publisher · View at Google Scholar
  81. 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) γ 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. View at Publisher · View at Google Scholar
  82. E. Mueller, M. Smith, P. Sarraf et al., “Effects of ligand activation of peroxisome proliferator-activated receptor γ 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. View at Publisher · View at Google Scholar · View at PubMed
  83. A. L. Sabichi, V. Subbarayan, N. Llansa, S. M. Lippman, and D. G. Menter, “Peroxisome proliferator-activated receptor-γ suppresses cyclooxygenase-2 expression in human prostate cells,” Cancer Epidemiology Biomarkers & Prevention, vol. 13, no. 11, part 1, pp. 1704–1709, 2004. View at Google Scholar
  84. 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 PPARγ,” Cancer Research, vol. 65, no. 4, pp. 1561–1569, 2005. View at Publisher · View at Google Scholar · View at PubMed
  85. J.-I. Hisatake, T. Ikezoe, M. Carey, S. Holden, S. Tomoyasu, and H. P. Koeffler, “Down-regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor γ in human prostate cancer,” Cancer Research, vol. 60, no. 19, pp. 5494–5498, 2000. View at Google Scholar
  86. W. Wu, J. Celestino, M. R. Milam et al., “Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model,” International Journal of Gynecological Cancer, vol. 18, no. 2, pp. 329–338, 2008. View at Publisher · View at Google Scholar · View at PubMed
  87. A. Elnemr, T. Ohta, K. Iwata et al., “PPARgamma ligand (thiazolidinedione) induces growth arrest and differentiation markers of human pancreatic cancer cells,” International Journal of Oncology, vol. 17, no. 6, pp. 1157–1164, 2000. View at Google Scholar
  88. W. Motomura, T. Okumura, N. Takahashi, T. Obara, and Y. Kohgo, “Activation of peroxisome proliferator-activated receptor γ by troglitazone inhibits cell growth through the increase of p27Kip1 in human pancreatic carcinoma cells,” Cancer Research, vol. 60, no. 19, pp. 5558–5564, 2000. View at Google Scholar
  89. M. Toyota, Y. Miyazaki, S. Kitamura et al., “Peroxisome proliferator-activated receptor γ reduces the growth rate of pancreatic cancer cells through the reduction of cyclin D1,” Life Sciences, vol. 70, no. 13, pp. 1565–1575, 2002. View at Publisher · View at Google Scholar
  90. P. Tontonoz, S. Singer, B. M. Forman et al., “Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor γ 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. View at Publisher · View at Google Scholar
  91. G. Debrock, V. Vanhentenrijk, R. Sciot, M. Debiec-Rychter, R. Oyen, and A. Van Oosterom, “A phase II trial with rosiglitazone in liposarcoma patients,” British Journal of Cancer, vol. 89, no. 8, pp. 1409–1412, 2003. View at Publisher · View at Google Scholar · View at PubMed
  92. T. G. Kroll, P. Sarraf, L. Pecciarini et al., “PAX8-PPARγ1 fusion in oncogene human thyroid carcinoma,” Science, vol. 289, no. 5483, pp. 1357–1360, 2000. View at Publisher · View at Google Scholar
  93. W. T. Shen and W.-Y. Chung, “Treatment of thyroid cancer with histone deacetylase inhibitors and peroxisome proliferator-activated receptor-γ agonists,” Thyroid, vol. 15, no. 6, pp. 594–599, 2005. View at Publisher · View at Google Scholar · View at PubMed
  94. J. P. Klopper, W. R. Hays, V. Sharma, M. A. Baumbusch, J. M. Hershman, and B. R. Haugen, “Retinoid X receptor-γ and peroxisome proliferator-activated receptor-γ expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment,” Molecular Cancer Therapeutics, vol. 3, no. 8, pp. 1011–1120, 2004. View at Google Scholar
  95. R. Fabiani, A. De Bartolomeo, P. Rosignoli, M. Servili, G. F. Montedoro, and G. Morozzi, “Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis,” European Journal of Cancer Prevention, vol. 11, no. 4, pp. 351–358, 2002. View at Publisher · View at Google Scholar
  96. M. D'Incalci, W. P. Steward, and A. J. Gescher, “Use of cancer chemopreventive phytochemicals as antineoplastic agents,” The Lancet Oncology, vol. 6, no. 11, pp. 899–904, 2005. View at Publisher · View at Google Scholar · View at PubMed
  97. P. Lagiou, M. Rossi, A. Lagiou, A. Tzonou, C. La Vecchia, and D. Trichopoulos, “Flavonoid intake and liver cancer: a case-control study in Greece,” Cancer Causes & Control, pp. 1–6, 2008. View at Publisher · View at Google Scholar · View at PubMed
  98. J. Linseisen, S. Rohrmann, A. B. Miller et al., “Fruit and vegetable consumption and lung cancer risk: updated information from the European Prospective Investigation into Cancer and Nutrition (EPIC),” International Journal of Cancer, vol. 121, no. 5, pp. 1103–1114, 2007. View at Publisher · View at Google Scholar · View at PubMed
  99. J. K. S. Ko, W. C. Leung, W. K. Ho, and P. Chiu, “Herbal diterpenoids induce growth arrest and apoptosis in colon cancer cells with increased expression of the nonsteroidal anti-inflammatory drug-activated gene,” European Journal of Pharmacology, vol. 559, no. 1, pp. 1–13, 2007. View at Publisher · View at Google Scholar · View at PubMed
  100. S. Shishodia, G. Sethi, M. Konopleva, M. Andreeff, and B. B. Aggarwal, “A synthetic triterpenoid, CDDO-Me, inhibits IκBα kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor κB-regulated gene products in human leukemic cells,” Clinical Cancer Research, vol. 12, no. 6, pp. 1828–1838, 2006. View at Publisher · View at Google Scholar · View at PubMed
  101. V. Amico, V. Barresi, D. Condorelli, C. Spatafora, and C. Tringali, “Antiproliferative terpenoids from almond hulls (Prunus dulcis): identification and structure-activity relationships,” Journal of Agricultural and Food Chemistry, vol. 54, no. 3, pp. 810–814, 2006. View at Publisher · View at Google Scholar · View at PubMed
  102. C.-L. Hsieh, M.-H. Tseng, Y.-Y. Shao et al., “C35 terpenoids from the bark of Calocedrus macrolepis var. formosana with activity against human cancer cell lines,” Journal of Natural Products, vol. 69, no. 11, pp. 1611–1613, 2006. View at Publisher · View at Google Scholar · View at PubMed
  103. H. Lapillonne, M. Konopleva, T. Tsao et al., “Activation of peroxisome proliferator-activated receptor γ by a novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest and apoptosis in breast cancer cells,” Cancer Research, vol. 63, no. 18, pp. 5926–5939, 2003. View at Google Scholar
  104. S. Chintharlapalli, S. Papineni, I. Jutooru, A. McAlees, and S. Safe, “Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor γ agonists in colon cancer cells,” Molecular Cancer Therapeutics, vol. 6, no. 5, pp. 1588–1598, 2007. View at Publisher · View at Google Scholar · View at PubMed
  105. S. Chintharlapalli, S. Papineni, S. Liu et al., “2-cyano-lup-1-en-3-oxo-20-oic acid, a cyano derivative of betulinic acid, activates peroxisome proliferator-activated receptor γ in colon and pancreatic cancer cells,” Carcinogenesis, vol. 28, no. 11, pp. 2337–2346, 2007. View at Publisher · View at Google Scholar · View at PubMed
  106. C.-C. Ho, P.-H. Huang, H.-Y. Huang, Y.-H. Chen, P.-C. Yang, and S.-M. Hsu, “Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation,” American Journal of Pathology, vol. 161, no. 5, pp. 1647–1656, 2002. View at Google Scholar
  107. E. Burgermeister, L. Tencer, and M. Liscovitch, “Peroxisome proliferator-activated receptor-γ upregulates caveolin-1 and caveolin-2 expression in human carcinoma cells,” Oncogene, vol. 22, no. 25, pp. 3888–3900, 2003. View at Publisher · View at Google Scholar · View at PubMed
  108. M.-L. Ricketts, D. D. Moore, W. J. Banz, O. Mezei, and N. F. Shay, “Molecular mechanisms of action of the soy isoflavones includes activation of promiscuous nuclear receptors. A review,” The Journal of Nutritional Biochemistry, vol. 16, no. 6, pp. 321–330, 2005. View at Publisher · View at Google Scholar · View at PubMed
  109. Z.-C. Dang, V. Audinot, S. E. Papapoulos, J. A. Boutin, and C. W. G. M. Löwik, “Peroxisome proliferator-activated receptor γ (PPARγ) as a molecular target for the soy phytoestrogen genistein,” The Journal of Biological Chemistry, vol. 278, no. 2, pp. 962–967, 2003. View at Publisher · View at Google Scholar · View at PubMed
  110. Y.-C. Liang, S.-H. Tsai, D.-C. Tsai, S.-Y. Lin-Shiau, and J.-K. Lin, “Suppression of inducible cyclooxygenase and nitric oxide synthase through activation of peroxisome proliferator-activated receptor-γ by flavonoids in mouse macrophages,” FEBS Letters, vol. 496, no. 1, pp. 12–18, 2001. View at Publisher · View at Google Scholar
  111. L. Fischer, C. Mahoney, A. R. Jeffcoat et al., “Clinical characteristics and pharmacokinetics of purified soy isoflavones: multiple-dose administration to men with prostate neoplasia,” Nutrition and Cancer, vol. 48, no. 2, pp. 160–170, 2004. View at Publisher · View at Google Scholar
  112. N. B. Kumar, J. P. Krischer, K. Allen et al., “Safety of purified isoflavones in men with clinically localized prostate cancer,” Nutrition and Cancer, vol. 59, no. 2, pp. 169–175, 2007. View at Google Scholar
  113. N. B. Kumar, J. P. Krischer, K. Allen et al., “A phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer,” Nutrition and Cancer, vol. 59, no. 2, pp. 163–168, 2007. View at Google Scholar
  114. C. H. Takimoto, K. Glover, X. Huang et al., “Phase I pharmacokinetic and pharmacodynamic analysis of unconjugated soy isoflavones administered to individuals with cancer,” Cancer Epidemiology Biomarkers & Prevention, vol. 12, no. 11, part 1, pp. 1213–1221, 2003. View at Google Scholar
  115. M. Hosokawa, M. Kudo, H. Maeda, H. Kohno, T. Tanaka, and K. Miyashita, “Fucoxanthin induces apoptosis and enhances the antiproliferative effect of the PPARγ ligand, troglitazone, on colon cancer cells,” Biochimica et Biophysica Acta, vol. 1675, no. 1–3, pp. 113–119, 2004. View at Publisher · View at Google Scholar · View at PubMed
  116. M. Maggiora, M. Bologna, M. P. Cerù et al., “An overview of the effect of linoleic and conjugated-linoleic acids on the growth of several human tumor cell lines,” International Journal of Cancer, vol. 112, no. 6, pp. 909–919, 2004. View at Publisher · View at Google Scholar · View at PubMed
  117. C. Bocca, F. Bozzo, S. Francica, S. Colombatto, and A. Miglietta, “Involvement of PPARγ and E-cadherin/β-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. View at Publisher · View at Google Scholar · View at PubMed
  118. T. Tsuzuki and Y. Kawakami, “Tumor angiogenesis suppression by α-eleostearic acid, a linolenic acid isomer with a conjugated triene system, via peroxisome proliferator-activated receptor γ,” Carcinogenesis, vol. 29, no. 4, pp. 797–806, 2008. View at Publisher · View at Google Scholar · View at PubMed
  119. Y. Yasui, R. Suzuki, H. Kohno et al., “9trans,11trans conjugated linoleic acid inhibits the development of azoxymethane-induced colonic aberrant crypt foci in rats,” Nutrition and Cancer, vol. 59, no. 1, pp. 82–91, 2007. View at Google Scholar
  120. T. Sasaki, K. Yoshida, H. Shimura et al., “Inhibitory effect of linoleic acid on transformation of IEC6 intestinal cells by in vitro azoxymethane treatment,” International Journal of Cancer, vol. 118, no. 3, pp. 593–599, 2006. View at Publisher · View at Google Scholar · View at PubMed
  121. A. W. Bull, K. R. Steffensen, J. Leers, and J. J. Rafter, “Activation of PPAR γ in colon tumor cell lines by oxidized metabolites of linoleic acid, endogenous ligands for PPAR γ,” Carcinogenesis, vol. 24, no. 11, pp. 1717–1722, 2003. View at Publisher · View at Google Scholar · View at PubMed
  122. X. Zuo, Y. Wu, J. S. Morris et al., “Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity,” Oncogene, vol. 25, no. 8, pp. 1225–1241, 2006. View at Publisher · View at Google Scholar · View at PubMed
  123. C.-S. Kim, W.-H. Park, J.-Y. Park et al., “Capsaicin, a spicy component of hot pepper, induces apoptosis by activation of the peroxisome proliferator-activated receptor γ in HT-29 human colon cancer cells,” Journal of Medicinal Food, vol. 7, no. 3, pp. 267–273, 2004. View at Publisher · View at Google Scholar
  124. A. Mori, S. Lehmann, J. O'Kelly et al., “Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells,” Cancer Research, vol. 66, no. 6, pp. 3222–3229, 2006. View at Publisher · View at Google Scholar · View at PubMed
  125. H.-S. Jun, T. Park, C. K. Lee et al., “Capsaicin induced apoptosis of B16-F10 melanoma cells through down-regulation of Bcl-2,” Food and Chemical Toxicology, vol. 45, no. 5, pp. 708–715, 2007. View at Publisher · View at Google Scholar · View at PubMed
  126. Y.-J. Surh and S. S. Lee, “Capsaicin in hot chili pepper: carcinogen, co-carcinogen or anticarcinogen?,” Food and Chemical Toxicology, vol. 34, no. 3, pp. 313–316, 1996. View at Publisher · View at Google Scholar
  127. S. I. Yoshitani, T. Tanaka, H. Kohno, and S. Takashima, “Chemoprevention of azoxymethane-induced rat colon carcinogenesis by dietary capsaicin and rotenone,” International Journal of Oncology, vol. 19, no. 5, pp. 929–939, 2001. View at Google Scholar
  128. M. L. Clapper, C. E. Szarka, G. R. Pfeiffer et al., “Preclinical and clinical evaluation of broccoli supplements as inducers of glutathione S-transferase activity,” Clinical Cancer Research, vol. 3, no. 1, pp. 25–30, 1997. View at Google Scholar
  129. R. A. Sharma, C. R. Ireson, R. D. Verschoyle et al., “Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels,” Clinical Cancer Research, vol. 7, no. 5, pp. 1452–1458, 2001. View at Google Scholar
  130. E. Y. Park, I. J. Cho, and S. G. Kim, “Transactivation of the PPAR-responsive enhancer module in chemopreventive glutathione S-transferase gene by the peroxisome proliferator-activated receptor-γ and retinoid X receptor heterodimer,” Cancer Research, vol. 64, no. 10, pp. 3701–3713, 2004. View at Publisher · View at Google Scholar · View at PubMed