Review Article | Open Access
Current Understanding of the Role of PPAR in Gastrointestinal Cancers
Numerous studies have indicated that PPAR plays multiple roles such as in inflammation, cell cycle control, cell proliferation, apoptosis, and carcinogenesis, thus PPAR contributes to the homeostasis. Many in vitro studies have showed that ligand-induced activation of PPAR possess antitumor effect in many cancers including CRC. However, the role of PPAR in gastrointestinal cancers, especially in colorectal cancer, is rather controversial. Nevertheless, some recent studies with the positive results on the possible application of PPAR ligands, such as Bezafibrate or Rosiglitazone in gastrointestinal cancers, have suggested a potential usefulness of PPAR agonists in cancer prevention and therapy. In this review, the authors discuss the recent developments in the role of PPAR in gastrointestinal cancers.
1. An Overview of PPAR Family
Peroxisome proliferator-activated receptor (PPAR) is a member of a family of nuclear hormone receptors that consists of three isoforms: PPAR, PPAR, and PPAR (also known as PPAR). Within this family are also retinoid X receptor (RXR), vitamin D receptor, and the thyroid hormone receptor. PPARs act as a ligand-activated transcription factor and are involved in many different biological functions. Extensive study of PPARs was probably sparkled by the identification of PPAR in 1990 , which was soon followed by the identification of two other members PPAR and PPAR [2, 3]. Each isoform of PPARs is encoded by a separate gene and exhibits different tissue distribution patterns. For example, PPAR is principally expressed in tissues that exhibit a high rate of fatty acid metabolism (e.g., brown adipose tissue, liver, kidney, and heart) and is the primary target for the fibrate class of drugs . PPAR is ubiquitously expressed in many tissues, and its physiological roles are multiple, including but may not be limited to lipid trafficking [5, 6], blastocyst implantation , wound healing , and the regulation of fatty acid catabolism and energy homeostasis [9, 10]. PPAR is richly expressed in adipose tissue, intestinal epithelial cells [11, 12], and macrophages. Low level of PPAR has also been found in skeletal muscle .
Like other nuclear receptors (NRs), all PPARs share a similar modular structure with functionally distinct domains called A/B (ligand-independent activation domain), C (DNA binding domain), D (hinge domain), and E/F (ligand-binding domain, LBD) (Owen et al. ). The N-terminal domain A/B has been relatively well conserved through evolution, whereas the C domain is the most conserved of all the functional domains. The less conserved domain D functions as a flexible hinge between the C and E/F domains and contains a sequence recognized by transporting proteins. Some of the amino acids are involved in the activities of nearby domains, leading to the dimerization and recognition of the target DNA sequences (Owen et al. ). The largest domain is the LBD located at the C-terminus , which is responsible for the binding of a specific ligand to PAR receptors, and subsequent activation of PPAR through binding to peroxisome proliferators response elements (PPREs) on the promoter region of the target genes. Thus, LBD is the major functionally related domain of the PPARs.
PPARs seem to regulate gene transcription by two mechanisms: transactivation and protein-protein interaction with other transcription factors. Transactivation of PPARs is a DNA-dependent mechanism, which involves binding of the PPAR ligands and heterodimerization between PPARs and RXR (Retinoid X receptor) . The heterodimer between PPARs and RXR then binds to PPRE, resulting in stimulation of transcription. In contrast, the protein-protein interaction mechanism involves the activation of target genes through other transcription factors, such as AP1, NF-B, Smads, STATs, and NFATs. It is suggested that most of inhibitory effects of PPARs are mediated by this mechanism [17, 18].
In this review, we only focus on the controversial role of PPAR human gastrointestinal cancers.
In human, the PPAR gene is located on chromosome 3 at position 3p25.2 . Two isoforms of PPAR have been identified: PPAR1 and PPAR2. These two isoforms only differ in their N termini sequences: PPAR2 protein contains an additional 30 N-terminal amino acids, but is otherwise identical to PPAR1. Both PPAR1 and PPAR2 N termini function as translational initiators, but the activity of PPAR2 is higher than that of PPAR1, suggesting that PPAR1 and PPAR2 N termini have distinct activation capacities, and perhaps may have different functions. PPAR2 is predominantly expressed in adipose tissue, and it has been demonstrated that PPAR2 N termini is more important in the process of adipocyte differentiation and metabolism [20, 21]. In contrast, PPAR1 is relatively stable and expressed at very high levels in the gastrointestinal epithelium [12, 22, 23], and low levels were observed in many other tissues .
The function of PPAR relies on its interactions with a coactivator or corepressor. Binding of PPAR to a coactivator affects the chromatin structure through acetylation of histones, whereas binding of PPAR to a corepressor alters the chromatin structure through deacetylation of histones. Both coactivators and corepressors are highly versatile and are not specific for particular PPAR subtypes . Binding of PPAR with coactivators may be either ligand-dependent or ligand-independent. Most coactivators interact with the LBD of NRs utilizing the LXXLL helical motifs in a ligand-dependent manner [26, 27]. In contrast, PPAR coactivator-1 (PGC-1) binds to the hinge domain of PPAR in a ligand-independent manner . In addition to the ligand-dependent and ligand-independent activation of PPAR, the activity of this transcription factor may also be modulated by posttranscriptional modification, such as phosphorylation [29–31].
3. PPAR Ligands
Over the past several years, various natural and synthetic PPAR ligands have been identified, and new ligands are under fast development.
In the broad sense, these ligands include specific PPAR agonists , PPAR partial agonists , and PPAR dual agonists . Synthetic PPAR agonists are able to modulate the adipocyte differentiation, and thus have been used as potential antidiabetic drugs [20, 32, 33]. The most commonly used PPAR agonists are Thiazolidinediones (TZDs), which include Troglitazone (Rezulin), Pioglitazone (Actos), and Rosiglitazone (Avandia).
TZDs are widely used in animal studies and clinical trials to investigate the role of PPAR. The roles of PPAR ligands are multiple. Some TZDs have been licensed for use in patients with Type 2 diabetes mellitus (T2DM) , some may benefit cardiovascular parameters, such as lipids, blood pressure, inflammatory biomarkers, endothelial function, and fibrinolytic state [36, 37]. Moreover, they have been successfully used in nondiabetic insulin-resistant conditions such as polycystic ovary syndrome [38, 39]. The synthetic PPAR ligands, however, are associated with various side effects, such as increased adiposity, edema, hepatotoxicity, and cardiac hypertrophy. Therefore, partial PPAR ligands with weaker side effects such as LSN862 have been developed [33, 40], and newer PPAR ligands that do not fall into the category of TZDs are under active development and their biological activities have been tested in various cancer cells. For example, the roles of LY293111 (Eli Lilly), CS-7017 (Sankyo), Spirolaxine (Sigma-Tau), and TZD-18 (Merck) have been investigated in various in vitro systems, and some are under clinical trials [41–45].
In addition to synthetic ligands, some endogenous (or natural) compounds are potent activators for PPAR. Among the natural PPAR ligands is cyclopentone 15-deoxy-E12,14-prostaglandin J2 (15d-PGJ2). This agent is probably the most potent endogenous PPAR ligand [46, 47] and has been widely used to study the role of PPAR activation in cancer cells .
4. Role of PPAR in Tumorigenesis of Gastrointestinal Cancers
As discussed earlier, PPAR is richly expressed in the normal gastrointestinal epithelium. Significantly high level of PPAR has been observed in the highly differentiated epithelial cells of the proximal colon [11, 12] and small intestine [12, 49]. In small intestine, PPAR is particularly expressed at the crypt/villus junction where small intestine epithelial cells cease to proliferate and undergo differentiation to mature to functional villus epithelial cells. These observations indicate that PPAR might play an important role in the regulation of differentiation of gastrointestinal epithelial cells. The fact that PPAR is expressed at a much higher level in the proximal colon than in distal colon implies that PPAR may play a complex role in the colon. The mechanisms by which PPAR regulates the differentiation of human gastrointestinal epithelial cells are not yet clear, but may involve a collaboration of PPAR with the transcription factor Hic5 as the transactivation of Hic5 by PPAR was shown to promote differentiation of intestinal epithelial cells during embryonic development .
The expression pattern of PPAR in colon cancer has been previously reported. Loss-of-function mutations to PPAR have been reported to be associated with increased propensity of human colon cancers  although the mutation of PPAR is very rare . Many in vitro studies have revealed that activation of PPAR inhibits proliferation and induces apoptosis of some colon cancer cell lines [53–60]. Compatible with these findings, heteroxygous loss of PPAR increases the susceptibility of colon and stomach into carcinogen-induced colon cancer and gastric cancer, respectively, [61–63]. Biallelic knockout of PPAR in colonic epithelial cells resulted in increased tumor incidence and tumor size in mice , and Pioglitazone suppressed colon tumor growth in mice in a dose-dependent manner [65–67]. Similar results were reported in studies conducted in other animal models. Troglitazone inhibited the formation of preneoplastic colonic aberrant crypt foci (ACF) in rats treated with either AOM or the combination of AOM with dextran suflate (DSS) [68, 69]. Several PPAR ligands including pioglitazone, rosiglitazone, and RS5444 have been reported to inhibit ACF formation in AOM-mediated colon cancer models [12, 67]. All these studies have suggested that PPAR functions as a tumor-suppressor gene and it might be involved in cancer suppression under the physiological conditions.
Carcinogenesis usually results from an imbalanced cell proliferation and apoptosis. The inhibitory effect of PPAR activation on colon cancer could be attributed to several mechanisms. For example, ligands-induced activation of PPAR was found to inhibit phosphatidylinositol 3-kinase (PI3K)/Akt signaling and retinoblastoma protein (Rb) dephosphorylation , induce expression of cyclin D1  and Bcl-xl/Bcl-2 , upregulate p21 and p27 [73–75], interact with XIAP , upregulate PTEN , and enhance the sensitivity of tumor cells to tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced cell death . Inhibition of hyperlipidemia, a well-established oncogenic factor for colon cancer, has also been proposed as one of the mechanisms responsible for the inhibitory effect of PPAR ligand on colon cancer [65, 66].
Although induction of apoptosis by PPAR agonists has been frequently suggested as one of the mechanisms responsible for their anticancer effects, it is less clear and perhaps controversial whether PPAR-induced apoptosis is actually receptor-mediated, or apoptosis simply occurs as an off target effect of PPAR agonists.
To complicate the issues even further is the fact that the inhibitory effect of PPAR activation on colon cancer formation does not have a universal support. For example, two PPAR agonists, troglitazone and rosigliatzone, have been reported to promote gastrointestinal tumorigenesis in C57BL/6J mice [11, 79], raising the serious concerns about the possibility that individuals who are on TZDs for T2DM might be at risk for colon cancer. These results were not able to be reproduced by other studies [65, 66]. On the contrary, long-term treatment with high concentrations of TZDs was found to increase the frequency of caecal tumors in wild-type C57BL/6J and C57BL/6J / double mutant mice . Part of the explanation is that in these mouse model studies, the doses of TZDs used were far greater than the doses that can be tolerated in human. Also, to add to the complexity of the role of PPAR in colon carcinogenesis, it has been reported that many TZDs may activate PPAR independent of PPAR receptor [72, 76, 81–84] but may require the presence of APC gene .
The contradictory results reported in these studies have clearly reflected the complexity of the role of PPAR in colon carcinogenesis. Large-scale in vivo studies using not only PPAR activators or inhibitors but also in knockout mice, especially colon specific knockout of PPAR, would generate more valuable data.
5. Role of PPAR during Anti-Inflammatory Process
In recent years, the causative link between inflammation and cancer has attracted considerable attention. The mechanism and molecular pathways of chronic inflammation leading to CRC development have been discussed in much detail in a recent review . It has been commonly agreed that in the development of CRC, inflammatory bowel diseases (IBD, which includes ulcerative colitis and Crohn’s disease) are among the major risk factors. These risk factors are particularly important in children and young adults of less than 30 years of age [86, 87].
There is an ample amount of evidence suggesting a role of PPAR in inflammatory processes. PPAR expression is reduced in ulcerative colitis . PPAR has been identified as anti-inflammatory molecules in IBD . Mice with a targeted disruption or elimination of the PPAR gene in intestinal epithelial cells showed an increased susceptibility to dextran sulfate sodium- (DSS-) induced IBD .
As macrophages play important role in the anti-inflammatory effect in the colon, its correlation with PPAR has been actively studied. It has been shown that mice with a targeted disruption of the PPAR gene in the macrophages of the intestinal epithelia also showed an increased susceptibility to DSS-induced IBD [90, 91], suggesting an important anti-inflammatory role of PPAR.
However, 5-aminosalicylic acid (5-ASA) is an anti-inflammatory drug widely used in the treatment of IBD. It has been reported that 5-ASA could bind to and activate PPAR . Binding of 5-ASA to PPAR receptor was found to be similar to the crystal orientation of the TZD head group of rosiglitazone. These observations indicated that 5-ASA exerted its anti-inflammatory effect through activating PPAR pathway. Based on these observations, PPAR ligands have been considered a group of potentially useful therapeutic agents for CRC and IBD [93, 94]. In a clinical trial, rosiglitazone was found to produce clinical and endoscopic remission of patients with ulcerative colitis in the majority of patients although this study was limited by its low number of patients .
Nonsteroidal anti-inflammatory drugs (NSAIDs) are also a group of PPAR activators. These agents are a widely used as anti-inflammatory drugs and pain killers. These agents can inhibit cyclooxygenase (COX) enzymes , and have a chemopreventive effect in various cancers, including CRC and gastric cancer [97, 98]. It has been reported that the chemopreventive effect of NSAIDs in gastrointestinal cancers was mechanistically attributable to their ability to activate PPAR.
It is now widely accepted that activation of PPAR may be an important mechanism responsible for the anti-inflammatory, and anticancer effects of most, if not all Cox inhibitors. For example, Curcumin, a widely recognized dietary agent with a strong ability to inhibit NF-B and COX-2, was found to activate the PPAR pathway in colon cancer . Other COX-2 inhibitors such as indomethacin and sulindac sulphide also were shown to activate PPAR pathways . In addition, inhibition of Cox-2 and activation of PPAR may have synergistic effect in inhibiting the growth of certain cancers such as pancreatic cancer .
The mechanisms by which COX inhibition leads to PPAR activation are not clearly defined, but may be possibly due to antagonizing NF-B activity, suppressing IL-8 and iNOS expressions, or increased production of prostaglandins derivertives such as 15d-PGJ2 [102, 103].
Overall, those data suggested that activation of PPAR exerts an anticancer effect partially through anti-inflammatory function.
6. Role of PPAR in Epithelial Mesenchymal Transition (EMT) and Tumor Invasion
Metastasis is a subsequent behavior of all malignant tumors, and often the cause of cancer mortality. EMT plays an important role during tumor metastasis. Some of the proteins involved in EMT could be utilized as potential prognostic markers or therapeutic targets.
EMT is regulated by multiple signaling pathways . The process starts from ligand-induced activation of tyrosine kinase receptors. The important ligands that may activate the tyrosine kinase receptors include epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (ILGF), and hepatocyte growth factor (HGF). Binding of these ligands to receptors alters the functions of some of the down-stream target genes: downregulation of the E-cadherin gene via the transcription factor Snail pathway; or directly affects cell adhesion and/or the cytoskeletal dynamics. Notch, Hedgehog, and NF-B signaling pathways have also been found to be involved in EMT.
It has been reported that PPAR promotes EMT by Rho GTPase-dependent activation of ERK1/2 in intestinal epithelial cells . RS5444 (a novel third-generation thiazolidinedione derivative) caused dramatic changes in cellular morphology, which were associated with increased motility and diminished cellular adherence in nontransformed rat intestinal epithelial cells (RIEs). These data suggest novel effects of PPAR on cell-cell and cell-matrix interactions . However, the precise role and mechanism by which PPAR regulates EMT and cancer metastasis are not yet well defined.
7. Role of PPAR in Angiogenesis
Angiogenesis plays an important role in the development and metastasis of all solid cancers. The regulatory role of PPAR in angiogenesis has been demonstrated in vitro and in vivo, as reviewed in details elsewhere [48, 106]. The effect of PPAR ligands on angiogenesis is bidirectional, possibly depends on cell types and specific pathways involved. Most of the studies showed that PPAR ligands inhibit angiogenesis, but opposite results have been reported. For example, 15d-PGJ2 inhibits angiogenesis via upregulation of HGF, VEGF, Flt-1 (VEGF receptor-1), and Flk/KDR (VEGF receptor-2). The same agent may also stimulate angiogenesis via the induction of heme oxygenase-1 (HO-1), endothelial nitric-oxide synthase, and hypoxia-inducible factor-1a (HIF-1) . Large-scale studies will have to be conducted to reveal the role of PPAR ligands in angiogenesis in a particular cancer.
8. Current Clinical Trials
Although many in vitro and in vivo data have demonstrated a potential therapeutic role of PPAR ligands in many cancers, the results from clinical trials are limited and the efficacy of PPAR ligands in most cancers was less satisfactory. The poor outcome may be partially related to the fact that most of these clinical trails that turned out to be negative on therapeutic effect were conducted in patients with refractory and advanced solid tumors, which are notoriously refractory to most of the available therapeutic approaches.
Table 1 lists some of the clinical trials on treatment of different human cancers by PPAR ligands. From these data, it is probably more plausible to designate PPAR ligands as a group of biological modifier in human cancers rather than therapeutic agents.
PPAR agonists are generally well tolerated. The major adverse effects are gastrointestinal toxicity, include diarrhea, vomiting, and abdominal pain [44, 45]. Certain TZDs, such as troglitazone, has been removed from clinical use because of the severe side effects. Overall, it is still inconclusive to state a definite therapeutic role of PPAR agonists in gastrointestinal cancers.
In summary, role of PPAR in CRC is rather controversial. PPAR ligands may exert therapeutic effects on colon cancer through a PPAR-dependent and a PPAR-independent pathway. The therapeutic effects of the current PPAR ligands in colon cancer are less optimal. Thus, new PPAR ligands are currently under development. Exploration of combinational therapy using PPAR ligands and other therapeutic drugs should be encouraged.
The studies reported in this review article were partially supported by the University of Hong Kong Seed Funding programs (Grant code: 10208191.49710.20600.301.01).
- 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.
- R. A. Graves, P. Tontonoz, and B. M. Spiegelman, “Analysis of a tissue-specific enhancer: ARF6 regulates adipogenic gene expression,” Molecular and Cellular Biology, vol. 12, no. 3, pp. 1202–1208, 1992.
- Y. Zhu, K. Alvares, Q. Huang, M. S. Rao, and J. K. Reddy, “Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver,” Journal of Biological Chemistry, vol. 268, no. 36, pp. 26817–26820, 1993.
- T. M. Willson, P. J. Brown, D. D. Sternbach et al., “The PPARs: fro orphan receptors to drug discovery,” Journal of Medicinal Chemistry, vol. 43, pp. 527–550, 2000.
- W. R. Oliver Jr., J. L. Shenk, M. R. Snaith et al., “Selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, pp. 5306–5311, 2001.
- A. Chawla, C.-H. Lee, Y. Barak et al., “PPAR is a very low-density lipoprotein sensor in macrophages,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 3, pp. 1268–1273, 2003.
- H. Lim and S. K. Dey, “PPAR functions as a prostacyclin receptor in blastocyst implantation,” Trends in Endocrinology and Metabolism, vol. 11, no. 4, pp. 137–142, 2000.
- N. S. Tan, L. Michalik, N. Noy et al., “Critical roles of PPAR / in keratinocyte response to inflammation,” Genes & Development, vol. 15, no. 24, pp. 3263–3277, 2001.
- J. M. Peters, S. S. T. Lee, W. Li et al., “Growths, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor (),” Molecular and Cellular Biology, vol. 20, no. 14, pp. 5119–5128, 2000.
- Y.-X. Wang, C.-H. Lee, S. Tiep et al., “Peroxisome-proliferator-activated receptor activates fat metabolism to prevent obesity,” Cell, vol. 113, no. 2, pp. 159–170, 2003.
- 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.
- W. Su, C. R. Bush, B. M. Necela et al., “Differential expression, distribution, and function of PPAR- in the proximal and distal colon,” Physiological Genomics, vol. 30, no. 3, pp. 342–353, 2007.
- C. G. Perry and J. R. Petrie, “Insulin-sensitising agents: beyond thiazolidinediones,” Expert Opinion on Emerging Drugs, vol. 7, no. 1, pp. 165–174, 2002.
- G. I. Owen and A. Zelent, “Origins and evolutionary diversification of the nuclear receptor superfamily,” Cellular and Molecular Life Sciences, vol. 57, no. 5, pp. 809–827, 2000.
- R. T. Nolte, G. B. Wisely, S. Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-,” Nature, vol. 395, no. 6698, pp. 137–143, 1998.
- 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.
- H. Yki-Järvinen, “Thiazolidinediones,” The New England Journal of Medicine, vol. 351, no. 11, pp. 1106–1118, 2004.
- E. A. Thompson, “PPAR physiology and pathology in gastrointestinal epithelial cells,” Molecules and Cells, vol. 24, no. 2, pp. 167–176, 2007.
- M. E. Greene, B. Blumberg, O. W. McBride et al., “Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping,” Gene Expression, vol. 4, no. 4-5, pp. 281–299, 1995.
- P. Tontonoz, E. Hu, R. A. Graves, A. I. Budavari, and B. M. Spiegelman, “mPPAR2: tissue-specific regulator of an adipocyte enhancer,” Genes and Development, vol. 8, no. 10, pp. 1224–1234, 1994.
- A. Werman, A. Hollenberg, G. Solanes, C. Bjørbæk, A. J. Vidal-Puig, and J. S. Flier, “Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor (PPAR). Differential activity of PPAR1 and -2 isoforms and influence of insulin,” Journal of Biological Chemistry, vol. 272, no. 32, pp. 20230–20235, 1997.
- L. Fajas, D. Auboeuf, E. Raspé et al., “The organization, promoter analysis, and expression of the human PPAR gene,” Journal of Biological Chemistry, vol. 272, no. 30, pp. 18779–18789, 1997.
- 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 PPAR2 versus PPAR1 and activation with retinoid X receptor agonists and antagonists,” Journal of Biological Chemistry, vol. 272, no. 12, pp. 8071–8076, 1997.
- A. J. Vidal-Puig, R. V. Considine, M. Jimenez-Liñan et al., “Peroxisome proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss, and regulation by insulin and glucocorticoids,” Journal of Clinical Investigation, vol. 99, no. 10, pp. 2416–2422, 1997.
- A. Zieleniak, M. Wójcik, and L. A. Woźniak, “Structure and physiological functions of the human peroxisome proliferator-activated receptor ,” Archivum Immunologiae et Therapiae Experimentalis, vol. 56, no. 5, pp. 331–345, 2008.
- D. M. Heery, E. Kalkhoven, S. Hoare, and M. G. Parker, “A signature motif in transcriptional co-activators mediates binding to nuclear receptors,” Nature, vol. 387, no. 6634, pp. 733–736, 1997.
- E. M. McInerney, D. W. Rose, S. E. Flynn et al., “Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation,” Genes & Development, vol. 12, no. 21, pp. 3357–3368, 1998.
- P. Puigserver, Z. Wu, C. W. Park, R. Graves, M. Wright, and B. M. Spiegelman, “A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis,” Cell, vol. 92, no. 6, pp. 829–839, 1998.
- M. Adams, M. J. Reginato, D. Shao, M. A. Lazar, and V. K. Chatterjee, “Transcriptional activation by peroxisome proliferator-activated receptor is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site,” Journal of Biological Chemistry, vol. 272, no. 8, pp. 5128–5132, 1997.
- H. S. Camp and S. R. Tafuri, “Regulation of peroxisome proliferator-activated receptor activity by mitogen-activated protein kinase,” The Journal of Biological Chemistry, vol. 272, pp. 10811–10816, 1997.
- E. Hu, J. B. Kim, P. Sarraf, and B. M. Spiegelman, “Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPAR,” Science, vol. 274, no. 5295, pp. 2100–2103, 1996.
- J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor (PPAR),” Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995.
- J. M. Lehmann, J. M. Lenhard, B. B. Oliver, G. M. Ringold, and S. A. Kliewer, “Peroxisome proliferator-activated receptors and are activated by indomethacin and other non-steroidal anti-inflammatory drugs,” Journal of Biological Chemistry, vol. 272, no. 6, pp. 3406–3410, 1997.
- H. E. Xu, M. H. Lambert, V. G. Montana et al., “Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 24, pp. 13919–13924, 2001.
- F. Chiarelli and D. Di Marzio, “Peroxisome proliferator-activated receptor- agonists and diabetes: current evidence and future perspectives,” Vascular Health and Risk Management, vol. 4, no. 2, pp. 297–304, 2008.
- A. A. Parulkar, M. L. Pendergrass, R. Granda-Ayala, T. R. Lee, and V. A. Fonseca, “Nonhypoglycemic effects of thiazolidinediones,” Annals of Internal Medicine, vol. 134, no. 1, pp. 61–71, 2001.
- S. M. Haffner, A. S. Greenbeg, W. M. Weston et al., “Effects of rosiglitazone treatment on non-traditional markers of cardiovascular disease in patients with type 2 diabetes mellitus,” Circulation, vol. 106, pp. 679–684, 2002.
- D. Romualdi, M. Guido, M. Ciampelli et al., “Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome,” Human Reproduction, vol. 18, no. 6, pp. 1210–1218, 2003.
- D. Glintborg, R. K. Støving, C. Hagen et al., “Pioglitazone treatment increases spontaneous growth hormone (GH) secretion and stimulated GH levels in polycystic ovary syndrome,” The Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 10, pp. 5605–5612, 2005.
- A. Reifel-Miller, K. Otto, E. Hawkins et al., “A peroxisome proliferator-activated receptor / dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia,” Molecular Endocrinology, vol. 19, no. 6, pp. 1593–1605, 2005.
- W.-G. Tong, X.-Z. Ding, R. Hennig et al., “Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells,” Clinical Cancer Research, vol. 8, no. 10, pp. 3232–3242, 2002.
- J. A. Copland, S. Kurakata, K. Fujiwara et al., “A novel high affinity PPAR- agonist inhibits human anaplastic thyroid tumour growth,” in Proceedings of the AACR Annual Meeting, Orlando, Fla, USA, 2004, LB-17.
- D.-C. Liu, C.-B. Zang, H.-Y. Liu, K. Possinger, S.-G. Fan, and E. Elstner, “A novel PPAR alpha/gamma dual agonist inhibits cell growth and induces apoptosis in human glioblastoma T98G cells,” Acta Pharmacologica Sinica, vol. 25, no. 10, pp. 1312–1319, 2004.
- G. K. Schwartz, A. Weitzman, E. O'Reilly et al., “Phase I and pharmacokinetic study of LY293111, an orally bioavailable LTB4 receptor antagonist, in patients with advanced solid tumors,” Journal of Clinical Oncology, vol. 23, no. 23, pp. 5365–5373, 2005.
- T. Baetz, E. Eisenhauer, L. Siu et al., “A phase I study of oral LY293111 given daily in combination with irinotecan in patients with solid tumours,” Investigational New Drugs, vol. 25, no. 3, pp. 217–225, 2007.
- S. A. Kliewer, J. M. Lenhard, T. M. Willson, I. Patel, D. C. Morris, and J. M. Lehmann, “A prostaglandin metabolite binds peroxisome proliferator-activated receptor and promotes adipocyte differentiation,” Cell, vol. 83, no. 5, pp. 813–819, 1995.
- 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.
- E.-H. Kim and Y.-J. Surh, “The role of 15-deoxy--prostaglandin , an endogenous ligand of peroxisome proliferator-activated receptor , in tumor angiogenesis,” Biochemical Pharmacology, vol. 76, no. 11, pp. 1544–1553, 2008.
- L. Chen, C. R. Bush, B. M. Necela et al., “RS5444, a novel PPAR agonist, regulates aspects of the differentiated phenotype in nontransformed intestinal epithelial cells,” Molecular and Cellular Endocrinology, vol. 251, no. 1-2, pp. 17–32, 2006.
- S. Drori, G. D. Girnun, L. Tou et al., “Hic-5 regulates an epithelial program mediated by PPAR,” Genes & Development, vol. 19, no. 3, pp. 362–375, 2005.
- P. Sarraf, E. Mueller, W. M. Smith et al., “Loss-of-function mutations in PPAR associated with human colon cancer,” Molecular Cell, vol. 3, no. 6, pp. 799–804, 1999.
- T. Ikezoe, C. W. Miller, S. Kawano et al., “Mutational analysis of the peroxisome proliferator-activated receptor in human malignancies,” Cancer Research, vol. 61, no. 13, pp. 5307–5310, 2001.
- J. A. Brockman, R. A. Gupta, and R. N. Dubois, “Activation of PPAR leads to inhibition of anchorage-independent growth of human colorectal cancer cells,” Gastroenterology, vol. 115, no. 5, pp. 1049–1055, 1998.
- P. Sarraf, E. Mueller, D. Jones et al., “Differentiation and reversal of malignant changes in colon cancer through PPAR,” Nature Medicine, vol. 4, no. 9, pp. 1046–1052, 1998.
- 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.
- G. G. Chen, J. F. Lee, S. H. Wang, U. P. F. Chan, P. C. Ip, and W. Y. Lau, “Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-B in human colon cancer,” Life Sciences, vol. 70, no. 22, pp. 2631–2646, 2002.
- T. Shimada, K. Kojima, K. Yoshiura, H. Hiraishi, and A. Terano, “Characteristics of the peroxisome proliferator activated receptor (PPAR) ligand induced apoptosis in colon cancer cells,” Gut, vol. 50, no. 5, pp. 658–664, 2002.
- R. A. Gupta, P. Sarraf, E. Mueller et al., “Peroxisome proliferator-activated receptor -mediated differentiation: a mutation in colon cancer cells reveals divergent and cell type-specific mechanisms,” Journal of Biological Chemistry, vol. 278, no. 25, pp. 22669–22677, 2003.
- T. Yoshizumi, T. Ohta, I. Ninomiya et al., “Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma 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.
- L. Qiao, Y. Dai, Q. Gu et al., “Down-regulation of X-linked inhibitor of apoptosis synergistically enhanced peroxisome proliferator-activated receptor ligand-induced growth inhibition in colon cancer,” Molecular Cancer Therapeutics, vol. 7, no. 7, pp. 2203–2211, 2008.
- G. D. Girnun, W. M. Smith, S. Drori et al., “APC-dependent suppression of colon carcinogenesis by PPAR,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 21, pp. 13771–13776, 2002.
- 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.
- Y. Dai, L. Qiao, W. C. Kwok et al., “Peroxisome proliferator-activated receptor- contributes to the inhibitory effects of embelin on colon carcinogenesis,” Cancer Research, vol. 69, no. 11, pp. 4776–4783, 2009.
- 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.
- N. Niho, M. Takahashi, T. Kitamura et al., “Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands,” Cancer Research, vol. 63, no. 18, pp. 6090–6095, 2003.
- N. Niho, M. Takahashi, Y. Shoji et al., “Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPAR ligand,” Cancer Science, vol. 94, no. 11, pp. 960–964, 2003.
- E. Osawa, A. Nakajima, K. Wada et al., “Peroxisome proliferator-activated receptor ligands suppress colon carcinogenesis induced by azoxymethane in mice,” Gastroenterology, vol. 124, no. 2, pp. 361–367, 2003.
- H. Kohno, S. Yoshitani, S. Takashima et al., “Troglitazone, a ligand for peroxisome proliferator-activated receptor , inhibits chemically-induced aberrant crypt foci in rats,” Japanese Journal of Cancer Research, vol. 92, no. 4, pp. 396–403, 2001.
- T. Tanaka, H. Kohno, S.-I. Yoshitani et al., “Ligands for peroxisome proliferator-activated receptors and inhibit chemically induced colitis and formation of aberrant crypt foci in rats,” Cancer Research, vol. 61, no. 6, pp. 2424–2428, 2001.
- L. Fajas, V. Egler, R. Reiter, S. Miard, A.-M. Lefebvre, and J. Auwerx, “PPAR controls cell proliferation and apoptosis in an RB-dependent manner,” Oncogene, vol. 22, no. 27, pp. 4186–4193, 2003.
- 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.
- 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.
- 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.
- H. Koga, S. Sakisaka, M. Harada et al., “Involvement of p21WAF1/Cip1, p27Kip1, and p18INK4c in troglitazone-induced cell-cycle arrest in human hepatoma cell lines,” Hepatology, vol. 33, no. 5, pp. 1087–1097, 2001.
- F. Chen and L. E. Harrison, “Ciglitazone-induced cellular anti-proliferation increases p27 kip1 protein levels through both increased transcriptional activity and inhibition of proteasome degradation,” Cellular Signalling, vol. 17, no. 7, pp. 809–816, 2005.
- L. Qiao, Y. Dai, Q. Gu et al., “Loss of XIAP sensitizes colon cancer cells to PPAR independent antitumor effects of troglitazone and 15-PG,” Cancer Letters, vol. 268, no. 2, pp. 260–271, 2008.
- Y. Dai, L. Qiao, W. C. Kwok et al., “Loss of XIAP sensitizes rosiglitazone-induced growth inhibition of colon cancer in vivo,” International Journal of Cancer, vol. 122, no. 12, pp. 2858–2863, 2008.
- Y. Kim, N. Suh, M. Sporn, and J. C. Reed, “An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis,” Journal of Biological Chemistry, vol. 277, no. 25, pp. 22320–22329, 2002.
- 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.
- K. Yang, K.-H. Fan, S. A. Lamprecht et al., “Peroxisome proliferator-activated receptor agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in double mutant mice,” International Journal of Cancer, vol. 116, no. 4, pp. 495–499, 2005.
- S. S. Palakurthi, H. Aktas, L. M. Grubissich, R. M. Mortensen, and J. A. Halperin, “Anticancer effects of thiazolidinediones are independent of peroxisome proliferator-activated receptor and mediated by inhibition of translation initiation,” Cancer Research, vol. 61, no. 16, pp. 6213–6218, 2001.
- 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.
- Y. Akasaki, G. Liu, H. H. Matundan et al., “A peroxisome proliferator-activated receptor- agonist, troglitazone, facilitates caspase-8 and -9 activities by increasing the enzymatic activity of protein-tyrosine phosphatase-1B on human glioma cells,” Journal of Biological Chemistry, vol. 281, no. 10, pp. 6165–6174, 2006.
- X. Li, X. Yang, Y. Xu et al., “Troglitazone inhibits cell proliferation by attenuation of epidermal growth factor receptor signaling independent of peroxisome proliferator-activated receptor ,” Cell Research, vol. 19, no. 6, pp. 720–732, 2009.
- J. Bassaganya-Riera, A. B. Carter, S. A. Misyak, and R. Hontecillas, “Dietary modulation of inflammation-induced colorectal cancer through PPAR,” PPAR Research, vol. 2009, Article ID 498352, 9 pages, 2009.
- S. H. Mir-Madjlessi, R. G. Farmer, K. A. Easley, and G. J. Beck, “Colorectal and extracolonic malignancy in ulcerative colitis,” Cancer, vol. 58, no. 7, pp. 1569–1574, 1986.
- A. Ekbom, C. Helmick, M. Zack, and H.-O. Adami, “Increased risk of large-bowel cancer in Crohn's disease with colonic involvement,” The Lancet, vol. 336, no. 8711, pp. 357–359, 1990.
- L. Dubuquoy, C. Rousseaux, X. Thuru et al., “PPAR as a new therapeutic target in inflammatory bowel diseases,” Gut, vol. 55, no. 9, pp. 1341–1349, 2006.
- M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor- is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998.
- Y. M. Shah, K. Morimura, and F. J. Gonzalez, “Expression of peroxisome proliferator-activated receptor- in macrophage suppresses experimentally induced colitis,” American Journal of Physiology, vol. 292, no. 2, pp. G657–G666, 2007.
- N. Watanabe, K. Ikuta, K. Okazaki et al., “Elimination of local macrophages in intestine prevents chronic colitis in interleukin-10-deficient mice,” Digestive Diseases and Sciences, vol. 48, no. 2, pp. 408–414, 2003.
- C. Rousseaux, B. Lefebvre, L. Dubuquoy et al., “Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-,” Journal of Experimental Medicine, vol. 201, no. 8, pp. 1205–1215, 2005.
- J. D. Ramakers, M. I. Verstege, G. Thuijls, A. A. Te Velde, R. P. Mensink, and J. Plat, “The PPAR agonist rosiglitazone impairs colonic inflammation in mice with experimental colitis,” Journal of Clinical Immunology, vol. 27, no. 3, pp. 275–283, 2007.
- C. Lytle, T. J. Tod, K. T. Vo, J. W. Lee, R. D. Atkinson, and D. S. Straus, “The peroxisome proliferator-activated receptor ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency,” Inflammatory Bowel Diseases, vol. 11, no. 3, pp. 231–243, 2005.
- J. D. Lewis, G. R. Lichtenstein, R. B. Stein et al., “An open-label trial of the PPAR ligand rosiglitazone for active ulcerative colitis,” American Journal of Gastroenterology, vol. 96, no. 12, pp. 3323–3328, 2001.
- R. G. Kurumbail, A. M. Stevens, J. K. Gierse et al., “Structural basis for selective inhibition of cyciooxygenase-2 by anti-inflammatory agents,” Nature, vol. 384, no. 6610, pp. 644–648, 1996.
- J. A. Baron, B. F. Cole, R. S. Sandler et al., “A randomized trial of aspirin to prevent colorectal adenomas,” The New England Journal of Medicine, vol. 348, no. 10, pp. 891–899, 2003.
- X. M. Fan, X. H. Jiang, Q. Gu et al., “Inhibition of Akt/PKB by a COX-2 inhibitor induces apoptosis in gastric cancer cells,” Digestion, vol. 73, no. 2-3, pp. 75–83, 2006.
- M. Zhang, C. Deng, J. Zheng, J. Xia, and D. Sheng, “Curcumin inhibits trinitrobenzene sulphonic acid-induced colitis in rats by activation of peroxisome proliferator-activated receptor gamma,” International Immunopharmacology, vol. 6, no. 8, pp. 1233–1242, 2006.
- A. S. Felts, C. Ji, J. B. Stafford et al., “Desmethyl derivatives of indomethacin and sulindac as probes for cyclooxygenase-dependent biology,” ACS Chemical Biology, vol. 2, no. 7, pp. 479–483, 2007.
- W.-H. Sun, G.-S. Chen, X.-L. Ou et al., “Inhibition of COX-2 and activation of peroxisome proliferator-activated receptor synergistically inhibits proliferation and induces apoptosis of human pancreatic carcinoma cells,” Cancer Letters, vol. 275, no. 2, pp. 247–255, 2009.
- O. Schröder, Y. Yudina, A. Sabirsh, N. Zahn, J. Z. Haeggström, and J. Stein, “15-deoxy--prostaglandin inhibits the expression of microsomal prostaglandin E synthase type 2 in colon cancer cells,” Journal of Lipid Research, vol. 47, no. 5, pp. 1071–1080, 2006.
- G. P. Vandoros, P. A. Konstantinopoulos, G. Sotiropoulou-Bonikou et al., “PPAR-gamma is expressed and NF-B pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas,” Journal of Cancer Research and Clinical Oncology, vol. 132, no. 2, pp. 76–84, 2006.
- M. Guarino, “Epithelial-mesenchymal transition and tumour invasion,” International Journal of Biochemistry and Cell Biology, vol. 39, no. 12, pp. 2153–2160, 2007.
- L. Chen, B. M. Necela, W. Su et al., “Peroxisome proliferator-activated receptor promotes epithelial to mesenchymal transformation by Rho GTPase-dependent activation of ERK1/2,” Journal of Biological Chemistry, vol. 281, no. 34, pp. 24575–24587, 2006.
- A. Margeli, G. Kouraklis, and S. Theocharis, “Peroxisome proliferator activated receptor- (PPAR-) ligands and angiogenesis,” Angiogenesis, vol. 6, no. 3, pp. 165–169, 2003.
Copyright © 2009 Bing Zou 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.