Colorectal cancer is one of the most common cancers in the world. Dietary fat intake is a major risk factor for colorectal cancer. Some nuclear hormone receptors play an important role in regulating nutrient metabolism and energy homeostasis. Among these receptors, special attention has been focused on the role of peroxisome proliferator-activated receptors (PPARs) in colorectal cancer, because PPARs are involved in regulation of lipid and carbohydrate metabolism. PPARs are ligand-activated intracellular transcription factors. The PPAR subfamily consists of three subtypes encoded by distinct genes named PPARα, PPARβ/δ, and PPARγ. PPARγ is the most extensively studied subtype of PPARs. Even though many investigators have studied the expression and clinical implications of PPARs in colorectal cancer, there are still many controversies about the role of PPARs in colorectal cancer. In this paper, the recent progresses in understanding the role of PPARs in colorectal cancer are summarized. 1. Introduction Colorectal cancer is one of the most common cancers in the world. Its incidence appears to be increasing, particularly in developed countries [1–3]. Colorectal carcinogenesis results from the loss of the normal regulatory pathways involved in cell proliferation and cell death. Especially, molecular alterations of multiple pathways including Wnt (Wingless type)/adenomatous polyposis coli (APC), cyclooxygenase-2 (COX-2), and Ras are known to play important roles in progression of colorectal cancer. Recent progresses in the development of new chemotherapeutic agents have improved the prognosis of colorectal cancer patients [4]. However, for most patients with advanced colorectal cancer, it is still difficult to achieve a complete remission, especially with surgery or chemotherapy. Therefore, significant effort has been exerted to identify novel drug targets for both the prevention and treatment of colorectal cancer. The peroxisome proliferator-activated receptors (PPARs) belong to members of the nuclear hormone receptor superfamily including receptors for steroid, retinoid, vitamin D, and thyroid hormones [5]. PPARs have received the attention of investigators interested in studying about the intracellular pathways that control signal transduction and gene transcription since their discovery in 1990. The name of PPARs was derived from its property to proliferate peroxisomes in rodent liver, where PPARα plays the major role. However, none of the PPARs could be contributed to peroxisome proliferation in humans [6]. PPARs are metabolic regulators involved in the
References
[1]
A. Jemal, F. Bray, M. M. Center, J. Ferlay, E. Ward, and D. Forman, “Global cancer statistics,” CA Cancer Journal for Clinicians, vol. 61, no. 2, pp. 69–90, 2011.
[2]
A. Jemal, R. Siegel, J. Xu, and E. Ward, “Cancer statistics, 2010,” CA Cancer Journal for Clinicians, vol. 60, no. 5, pp. 277–300, 2010.
[3]
D. M. Parkin, F. Bray, J. Ferlay, and P. Pisani, “Global cancer statistics, 2002,” CA Cancer Journal for Clinicians, vol. 55, no. 2, pp. 74–108, 2005.
[4]
J. Waters and D. Cunningham, “The changing face of chemotherapy in colorectal cancer,” British Journal of Cancer, vol. 84, no. 1, pp. 1–7, 2001.
[5]
D. J. Mangelsdorf, C. Thummel, M. Beato et al., “The nuclear receptor super-family: the second decade,” Cell, vol. 83, no. 6, pp. 835–839, 1995.
[6]
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.
[7]
K. Schoonjans, B. Staels, and J. Auwerx, “The peroxisome proliferator activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation,” Biochimica et Biophysica Acta, vol. 1302, no. 2, pp. 93–109, 1996.
[8]
T. M. Willson, P. J. Brown, D. D. Sternbach, and B. R. Henke, “The PPARs: from orphan receptors to drug discovery,” Journal of Medicinal Chemistry, vol. 43, no. 4, pp. 527–550, 2000.
[9]
J. I. Park, “The role of 15d-PGJ2, a natural ligand for peroxisome proliferator-activated receptor γ (PPARγ), in cancer,” in Cellular and Genetic Practices for Translational Medicine, pp. 169–195, Research Signpost, 2011.
[10]
R. Grau, C. Punzón, M. Fresno, and M. A. I？iguez, “Peroxisome-proliferator-activated receptor α agonists inhibit cyclo-oxygenase 2 and vascular endothelial growth factor transcriptional activation in human colorectal carcinoma cells via inhibition of activator protein-1,” Biochemical Journal, vol. 395, no. 1, pp. 81–88, 2006.
[11]
L. Rosenberg, J. R. Palmer, A. G. Zauber, M. E. Warshauer, P. D. Stolley, and S. Shapiro, “A hypothesis: nonsteroidal anti-inflammatory drugs reduce the incidence of large bowel cancer,” Journal of the National Cancer Institute, vol. 83, no. 5, pp. 355–358, 1991.
[12]
B. S. Reddy, C. V. Rao, and K. Seibert, “Evaluation of cyclooxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis,” Cancer Research, vol. 56, no. 20, pp. 4566–4569, 1996.
[13]
M. J. Thun, M. M. Namboodiri, and C. W. Heath Jr., “Aspirin use and reduced risk of fatal colon cancer,” The New England Journal of Medicine, vol. 325, no. 23, pp. 1593–1596, 1991.
[14]
R. F. A. Logan, J. Little, P. G. Hawtin, and J. D. Hardcastle, “Effect of aspirin and non-steroidal anti-inflammatory drugs on colorectal adenomas: case-control study of subjects participating in the Nottingham faecal occult blood screening programme,” British Medical Journal, vol. 307, no. 6899, pp. 285–289, 1993.
[15]
D. M. Schreinemachers and R. B. Everson, “Aspirin use and lung, colon, and breast cancer incidence in a prospective study,” Epidemiology, vol. 5, no. 2, pp. 138–146, 1994.
[16]
D. A. Kujubu, B. S. Fletcher, B. C. Varnum, R. W. Lim, and H. R. Herschman, “TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue,” The Journal of Biological Chemistry, vol. 266, no. 20, pp. 12866–12872, 1991.
[17]
D. A. Jones, D. P. Carlton, T. M. McIntyre, G. A. Zimmerman, and S. M. Prescott, “Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines,” The Journal of Biological Chemistry, vol. 268, no. 12, pp. 9049–9054, 1993.
[18]
R. N. DuBois, J. Awad, J. Morrow, L. J. Roberts II, and P. R. Bishop, “Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-α and phorbol ester,” Journal of Clinical Investigation, vol. 93, no. 2, pp. 493–498, 1994.
[19]
H. Inoue, C. Yokoyama, S. Hara, Y. Tone, and T. Tanabe, “Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element,” The Journal of Biological Chemistry, vol. 270, no. 42, pp. 24965–24971, 1995.
[20]
K. Subbaramaiah, N. Telang, J. T. Ramonetti et al., “Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells,” Cancer Research, vol. 56, no. 19, pp. 4424–4429, 1996.
[21]
J. R. Mestre, K. Subbaramaiah, P. G. Sacks et al., “Retinoids suppress epidermal growth factor-induced transcription of cyclooxygenase-2 in human oral squamous carcinoma cells,” Cancer Research, vol. 57, no. 14, pp. 2890–2895, 1997.
[22]
M. Tsujii, S. Kawano, and R. N. Dubois, “Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 7, pp. 3336–3340, 1997.
[23]
M. Tsujii and R. N. Dubois, “Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2,” Cell, vol. 83, no. 3, pp. 493–501, 1995.
[24]
M. Tsujii, S. Kawano, S. Tsuji, H. Sawaoka, M. Hori, and R. N. Dubois, “Cyclooxygenase regulates angiogenesis induced by colon cancer cells,” Cell, vol. 93, no. 5, pp. 705–716, 1998.
[25]
R. Masunaga, H. Kohno, D. K. Dhar et al., “Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients,” Clinical Cancer Research, vol. 6, no. 10, pp. 4064–4068, 2000.
[26]
P. A. Craven, J. Pfanstiel, and F. R. DeRubertis, “Role of activation of protein kinase C in the stimulation of colonic epithelial proliferation and reactive oxygen formation by bile acids,” Journal of Clinical Investigation, vol. 79, no. 2, pp. 532–541, 1987.
[27]
T. Narisawa, N. E. Magadia, J. H. Weisburger, and E. L. Wynder, “Promoting effect of bile acids on colon carcinogenesis after intrarectal instillation of N-methyl-N′-nitro-N-nitrosoguanidine in rats,” Journal of the National Cancer Institute, vol. 53, no. 4, pp. 1093–1097, 1974.
[28]
U. G. Allinger, G. K. Johansson, J. A. Gustafsson, and J. J. Rafter, “Shift from a mixed to a lactovegetarian diet: influence on acidic lipids in fecal water—a potential risk factor for colon cancer,” American Journal of Clinical Nutrition, vol. 50, no. 5, pp. 992–996, 1989.
[29]
M. Makishima, A. Y. Okamoto, J. J. Repa et al., “Identification of a nuclear receptor for bite acids,” Science, vol. 284, no. 5418, pp. 1362–1365, 1999.
[30]
D. J. Parks, S. G. Blanchard, R. K. Bledsoe et al., “Bile acids: natural ligands for an orphan nuclear receptor,” Science, vol. 284, no. 5418, pp. 1365–1368, 1999.
[31]
J. L. Staudinger, B. Goodwin, S. A. Jones et al., “The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 6, pp. 3369–3374, 2001.
[32]
M. Makishima, T. T. Lu, W. Xie et al., “Vitamin D receptor as an intestinal bile acid sensor,” Science, vol. 296, no. 5571, pp. 1313–1316, 2002.
[33]
H. Oshio, T. Abe, T. Onogawa et al., “Peroxisome proliferator-activated receptor α activates cyclooxygenase-2 gene transcription through bile acid transport in human colorectal cancer cell lines,” Journal of Gastroenterology, vol. 43, no. 7, pp. 538–549, 2008.
[34]
J. L. Tong, C. P. Zhang, F. Nie et al., “MicroRNA 506 regulates expression of PPARα in hydroxycamptothecin-resistant human colon cancer cells,” FEBS Letters, vol. 585, no. 22, pp. 3560–3568, 2011.
[35]
R. M. Evans, “The steroid and thyroid hormone receptor superfamily,” Science, vol. 240, no. 4854, pp. 889–895, 1988.
[36]
K. Schoonjans, G. Martin, B. Staels, and J. Auwerx, “Peroxisome proliferator-activated receptors, orphans with ligands and functions,” Current Opinion in Lipidology, vol. 8, no. 3, pp. 159–166, 1997.
[37]
J. J. Mansure, R. Nassim, and W. Kassouf, “Peroxisome proliferator-activated receptor γ in bladder cancer: a promising therapeutic target,” Cancer Biology and Therapy, vol. 8, no. 7, pp. 1–9, 2009.
[38]
R. N. Dubois, R. Gupta, J. Brockman, B. S. Reddy, S. L. Krakow, and M. A. Lazar, “The nuclear eicosanoid receptor, PPARγ, is aberrantly expressed in colonic cancers,” Carcinogenesis, vol. 19, no. 1, pp. 49–53, 1998.
[39]
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.
[40]
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.
[41]
T. Kubota, K. Koshizuka, E. A. Williamson et al., “Ligand for peroxisome proliferator-activated receptor γ (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo,” Cancer Research, vol. 58, no. 15, pp. 3344–3352, 1998.
[42]
A. Krishnan, S. A. Nair, and M. R. Pillai, “Biology of PPARγ in cancer: a critical review on existing lacunae,” Current Molecular Medicine, vol. 7, no. 6, pp. 532–540, 2007.
[43]
C. A. de la Lastra, S. Sánchez-Fidalgo, I. Villegas, and V. Motilva, “New pharmacological perspectives and therapeutic potential of PPAR-γ agonists,” Current Pharmaceutical Design, vol. 10, no. 28, pp. 3505–3524, 2004.
[44]
T. Wang, J. Xu, X. Yu, R. Yang, and Z. C. Han, “Peroxisome proliferator-activated receptor γ in malignant diseases,” Critical Reviews in Oncology/Hematology, vol. 58, no. 1, pp. 1–14, 2006.
[45]
P. Sarraf, E. Mueller, W. M. Smith et al., “Loss-of-function mutations in PPARγ associated with human colon cancer,” Molecular Cell, vol. 3, no. 6, pp. 799–804, 1999.
[46]
T. Ikezoe, C. W. Miller, S. Kawano et al., “Mutational analysis of the peroxisome proliferator-activated receptor γ in human malignancies,” Cancer Research, vol. 61, no. 13, pp. 5307–5310, 2001.
[47]
L. Patel, I. Pass, P. Coxon, C. P. Downes, S. A. Smith, and C. H. Macphee, “Tumor suppressor and anti-inflammatory actions of PPARγ agonists are mediated via upregulation of PTEN,” Current Biology, vol. 11, no. 10, pp. 764–768, 2001.
[48]
Y. Dai, L. Qiao, K. W. Chan 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.
[49]
D. Wang, W. Ning, D. Xie, L. Guo, and R. N. Dubois, “Peroxisome proliferator-activated receptor δ confers resistance to peroxisome proliferator-activated receptor γ-induced apoptosis in colorectal cancer cells,” Oncogene, vol. 31, no. 8, pp. 1013–1023, 2012.
[50]
L. Qiao, Y. Dai, Q. Gu et al., “Downregulation of X-linked inhibitor of apoptosis synergistically enhanced peroxisome proliferator-activated receptor γ ligand-induced growth inhibition in colon cancer,” Molecular Cancer Therapeutics, vol. 7, no. 7, pp. 2203–2211, 2008.
[51]
C. J. Lee, J. S. Han, C. Y. Seo et al., “Pioglitazone, a synthetic ligand for PPARγ, induces apoptosis in RB-deficient human colorectal cancer cells,” Apoptosis, vol. 11, no. 3, pp. 401–411, 2006.
[52]
J. O. Ban, D. H. Kwak, J. H. Oh et al., “Suppression of NF-κB and GSK-3β is involved in colon cancer cell growth inhibition by the PPAR agonist troglitazone,” Chemico-Biological Interactions, vol. 188, no. 1, pp. 75–85, 2010.
[53]
E. Kim, F. Chen, C. C. Wang, and L. E. Harrison, “CDK5 is a novel regulatory protein in PPARγ ligand-induced antiproliferation,” International Journal of Oncology, vol. 28, no. 1, pp. 191–194, 2006.
[54]
S. Kitamura, Y. Miyazaki, S. Hiraoka et al., “PPARγ agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells,” International Journal of Cancer, vol. 94, no. 3, pp. 335–342, 2001.
[55]
A. Chen and J. Xu, “Activation of PPARγ by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 288, no. 3, pp. G447–G456, 2005.
[56]
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.
[57]
F. Chen, E. Kim, C. C. Wang, and L. E. Harrison, “Ciglitazone-induced p27 gene transcriptional activity is mediated through Sp1 and is negatively regulated by the MAPK signaling pathway,” Cellular Signalling, vol. 17, no. 12, pp. 1572–1577, 2005.
[58]
Y. C. Zhi and C. C. Tseng, “15-Deoxy-Δ12,14 prostaglandin J2 upregulates krüppel-like factor 4 expression independently of peroxisome proliferator-activated receptor γ by activating the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signal transduction pathway in HT-29 colon cancer cells,” Molecular Pharmacology, vol. 68, no. 5, pp. 1203–1213, 2005.
[59]
J. Rageul, S. Mottier, A. Jarry et al., “KLF4-dependent, PPARγ-induced expression of GPA33 in colon cancer cell lines,” International Journal of Cancer, vol. 125, no. 12, pp. 2802–2809, 2009.
[60]
G. G. Chen, H. Xu, J. F. Y. Lee et al., “15-Hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathway,” International Journal of Cancer, vol. 107, no. 5, pp. 837–843, 2003.
[61]
G. G. Chen, J. F. Y. 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-κB in human colon cancer,” Life Sciences, vol. 70, no. 22, pp. 2631–2646, 2002.
[62]
C. Toaldo, S. Pizzimenti, A. Cerbone et al., “PPARγ ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network in colon cancer cells,” Journal of Cellular and Molecular Medicine, vol. 14, no. 6, pp. 1347–1357, 2010.
[63]
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.
[64]
Y. D. Dong, X. P. Wang, and K. Wu, “Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor γ involves angiogenesis inhibition,” World Journal of Gastroenterology, vol. 15, no. 4, pp. 441–448, 2009.
[65]
D. Shen, C. Deng, and M. Zhang, “Peroxisome proliferator-activated receptor γ agonists inhibit the proliferation and invasion of human colon cancer cells,” Postgraduate Medical Journal, vol. 83, no. 980, pp. 414–419, 2007.
[66]
S. Giri, R. Rattan, A. K. Singh, and I. Singh, “The 15-deoxy-Δ12,14-prostaglandin J2 inhibits the inflammatory response in primary rat astrocytes via downregulating multiple steps in phosphatidylinositol 3-kinase-Akt-NF-κB-p300 pathway independent of peroxisome proliferator-activated receptor γ,” Journal of Immunology, vol. 173, no. 8, pp. 5196–5208, 2004.
[67]
T. V. Petrova, K. T. Akama, and L. J. van Eldik, “Cyclopentenone prostaglandins suppress activation of microglia: downregulation of inducible nitric-oxide synthase by 15-deoxy-Δ12,14-prostaglandin J2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 8, pp. 4668–4673, 1999.
[68]
P. K. Chatterjee, N. S. A. Patel, S. Cuzzocrea et al., “The cyclopentenone prostaglandin 15-deoxy-Δ12,14- prostaglandin J2 ameliorates ischemic acute renal failure,” Cardiovascular Research, vol. 61, no. 3, pp. 630–643, 2004.
[69]
H. Inoue, T. Tanabe, and K. Umesono, “Feedback control of cyclooxygenase-2 expression through PPARγ,” The Journal of Biological Chemistry, vol. 275, no. 36, pp. 28028–28032, 2000.
[70]
H. Fahmi, J. P. Pelletier, F. Mineau, and J. Martel-Pelletier, “15d-PGJ2 is acting as a “dual agent” on the regulation of COX-2 expression in human osteoarthritic chondrocytes,” Osteoarthritis and Cartilage, vol. 10, no. 11, pp. 845–848, 2002.
[71]
K. Subbaramaiah, D. T. Lin, J. C. Hart, and A. J. Dannenberg, “Peroxisome proliferator-activated receptor γ ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300,” The Journal of Biological Chemistry, vol. 276, no. 15, pp. 12440–12448, 2001.
[72]
E. H. Kim and Y. J. Surh, “15-Deoxy-Δ12,14-prostaglandin J2 as a potential endogenous regulator of redox-sensitive transcription factors,” Biochemical Pharmacology, vol. 72, no. 11, pp. 1516–1528, 2006.
[73]
Y. Azuma, M. Shinohara, P. L. Wang, and K. Ohura, “15-Deoxy-Δ12,14-prostaglandin J2 inhibits IL-10 and IL-12 production by macrophages,” Biochemical and Biophysical Research Communications, vol. 283, no. 2, pp. 344–346, 2001.
[74]
K. M. Yamada and M. Araki, “Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis,” Journal of Cell Science, vol. 114, no. 13, pp. 2375–2382, 2001.
[75]
D. C. Altieri, “Validating survivin as a cancer therapeutic target,” Nature Reviews Cancer, vol. 3, no. 1, pp. 46–54, 2003.
[76]
H. Kawasaki, D. C. Altieri, C. D. Lu, M. Toyoda, T. Tenjo, and N. Tanigawa, “Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer,” Cancer Research, vol. 58, no. 22, pp. 5071–5074, 1998.
[77]
A. I. Sarela, N. Scott, J. Ramsdale, A. F. Markham, and P. J. Guillou, “Immunohistochemical detection of the anti-apoptosis protein, survivin, predicts survival after curative resection of stage II colorectal carcinomas,” Annals of Surgical Oncology, vol. 8, no. 4, pp. 305–310, 2001.
[78]
T. Kaufmann, A. Strasser, and P. J. Jost, “Fas death receptor signalling: roles of Bid and XIAP,” Cell Death and Differentiation, vol. 19, no. 1, pp. 42–50, 2012.
[79]
S. Ghosh, M. J. May, and E. B. Kopp, “NF-κB and rel proteins: evolutionarily conserved mediators of immune responses,” Annual Review of Immunology, vol. 16, pp. 225–260, 1998.
[80]
F. R. Greten, L. Eckmann, T. F. Greten et al., “IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer,” Cell, vol. 118, no. 3, pp. 285–296, 2004.
[81]
E. Pikarsky, R. M. Porat, I. Stein et al., “NF-κB functions as a tumour promoter in inflammation-associated cancer,” Nature, vol. 431, no. 7007, pp. 461–466, 2004.
[82]
A. Garg and B. B. Aggarwal, “Nuclear transcription factor-κB as a target for cancer drug development,” Leukemia, vol. 16, no. 6, pp. 1053–1068, 2002.
[83]
L. Fajas, V. Egler, R. Reiter, S. Miard, A. M. Lefebvre, and J. Auwerx, “PPARγ controls cell proliferation and apoptosis in an RB-dependent manner,” Oncogene, vol. 22, no. 27, pp. 4186–4193, 2003.
[84]
S. Lu, G. Yu, Y. Zhu, and M. C. Archer, “Cyclooxygenase-2 overexpression in MCF-10F human breast epithelial cells inhibits proliferation, apoptosis and differentiation, and causes partial transformation,” International Journal of Cancer, vol. 116, no. 6, pp. 847–852, 2005.
[85]
S. Gately and W. W. Li, “Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy,” Seminars in Oncology, vol. 31, no. 7, pp. 2–11, 2004.
[86]
D. T. Dang, J. Pevsner, and V. W. Yang, “The biology of the mammalian Krüppel-like family of transcription factors,” International Journal of Biochemistry and Cell Biology, vol. 32, no. 11-12, pp. 1103–1121, 2000.
[87]
J. L. Shie, Z. Y. Chen, M. J. O'Brien, R. G. Pestell, M. E. Lee, and C. C. Tseng, “Role of gut-enriched Krüppel-like factor in colonic cell growth and differentiation,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 279, no. 4, pp. G806–G814, 2000.
[88]
J. J. Bieker, “Krüppel-like factors: three fingers in many pies,” The Journal of Biological Chemistry, vol. 276, no. 37, pp. 34355–34358, 2001.
[89]
Z. Y. Chen, J. L. Shie, and C. C. Tseng, “Upregulation of gut-enriched krüppel-like factor by interferon-γ in human colon carcinoma cells,” FEBS Letters, vol. 477, no. 1-2, pp. 67–72, 2000.
[90]
D. T. Dang, X. Chen, J. Feng, M. Torbenson, L. H. Dang, and V. W. Yang, “Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity,” Oncogene, vol. 22, no. 22, pp. 3424–3430, 2003.
[91]
K. Dhaene, E. van Marck, and R. Parwaresch, “Telomeres, telomerase and cancer: an up-date,” Virchows Archiv, vol. 437, no. 1, pp. 1–16, 2000.
[92]
J. W. Shay and W. E. Wright, “Telomerase therapeutics for cancer: challenges and new directions,” Nature Reviews Drug Discovery, vol. 5, no. 7, pp. 577–584, 2006.
[93]
E. Hiyama, T. Yokoyama, N. Tatsumoto et al., “Telomerase activity in gastric cancer,” Cancer Research, vol. 55, no. 15, pp. 3258–3262, 1995.
[94]
C. Chadeneau, K. Hay, H. W. Hirte, S. Gallinger, and S. Bacchetti, “Telomerase activity associated with acquisition of malignancy in human colorectal cancer,” Cancer Research, vol. 55, no. 12, pp. 2533–2536, 1995.
[95]
A. G. Bodnar, M. Ouellette, M. Frolkis et al., “Extension of life-span by introduction of telomerase into normal human cells,” Science, vol. 279, no. 5349, pp. 349–352, 1998.
[96]
H. Vaziri and S. Benchimol, “Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span,” Current Biology, vol. 8, no. 5, pp. 279–282, 1998.
[97]
A. K. Meeker and A. M. de Marzo, “Recent advances in telomere biology: implications for human cancer,” Current Opinion in Oncology, vol. 16, no. 1, pp. 32–38, 2004.
[98]
C. P. Morales, S. E. Holt, M. Ouellette et al., “Absence of cancer-associated changes in human fibroblasts immortalized with telomerase,” Nature Genetics, vol. 21, no. 1, pp. 115–118, 1999.
[99]
W. C. Hahn, S. A. Stewart, M. W. Brooks et al., “Inhibition of telomerase limits the growth of human cancer cells,” Nature Medicine, vol. 5, no. 10, pp. 1164–1170, 1999.
[100]
F. Delhommeau, A. Thierry, D. Feneux et al., “Telomere dysfunction and telomerase reactivation in human leukemia cell lines after telomerase inhibition by the expression of a dominant-negative hTERT mutant,” Oncogene, vol. 21, no. 54, pp. 8262–8271, 2002.
[101]
H. Kawamata, M. Tachibana, T. Fujimori, and Y. Imai, “Differentiation-inducing therapy for solid tumors,” Current Pharmaceutical Design, vol. 12, no. 3, pp. 379–385, 2006.
[102]
W. Risau, “Mechanisms of angiogenesis,” Nature, vol. 386, no. 6626, pp. 671–674, 1997.
[103]
N. Ferrara, H. P. Gerber, and J. LeCouter, “The biology of VEGF and its receptors,” Nature Medicine, vol. 9, no. 6, pp. 669–676, 2003.
[104]
P. Carmeliet, “VEGF as a key mediator of angiogenesis in cancer,” Oncology, vol. 69, no. 3, pp. 4–10, 2005.
[105]
J. C. Lee, N. H. Chow, S. T. Wang, and S. M. Huang, “Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients,” European Journal of Cancer, vol. 36, no. 6, pp. 748–753, 2000.
[106]
R. T. P. Poon, S. T. Fan, and J. Wong, “Clinical implications of circulating angiogenic factors in cancer patients,” Journal of Clinical Oncology, vol. 19, no. 4, pp. 1207–1225, 2001.
[107]
M. D. Sternlicht and Z. Werb, “How matrix metalloproteinases regulate cell behavior,” Annual Review of Cell and Developmental Biology, vol. 17, pp. 463–516, 2001.
[108]
B. B. Aggarwal, S. Shishodia, S. K. Sandur, M. K. Pandey, and G. Sethi, “Inflammation and cancer: how hot is the link?” Biochemical Pharmacology, vol. 72, no. 11, pp. 1605–1621, 2006.
[109]
S. Minuzzo, L. Moserle, S. Indraccolo, and A. Amadori, “Angiogenesis meets immunology: cytokine gene therapy of cancer,” Molecular Aspects of Medicine, vol. 28, no. 1, pp. 59–86, 2007.
[110]
I. K. Choi, Y. H. Kim, J. S. Kim, and J. H. Seo, “PPAR-γ ligand promotes the growth of APC-mutated HT-29 human colon cancer cells in vitro and in vivo,” Investigational New Drugs, vol. 26, no. 3, pp. 283–288, 2008.
[111]
E. H. Kim, H. K. Na, D. H. Kim et al., “15-Deoxy-Δ12,14-prostaglandin J2 induces COX-2 expression through Akt-driven AP-1 activation in human breast cancer cells: a potential role of ROS,” Carcinogenesis, vol. 29, no. 4, pp. 688–695, 2008.
[112]
K. Yamakawa, M. Hosoi, H. Koyama et al., “Peroxisome proliferator-activated receptor-γ agonists increase vascular endothelial growth factor expression in human vascular smooth muscle cells,” Biochemical and Biophysical Research Communications, vol. 271, no. 3, pp. 571–574, 2000.
[113]
M. Inoue, H. Itoh, T. Tanaka et al., “Oxidized LDL regulates vascular endothelial growth factor expression in human macrophages and endothelial cells through activation of peroxisome proliferator-activated receptor-γ,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 4, pp. 560–566, 2001.
[114]
V. Chintalgattu, G. S. Harris, S. M. Akula, and L. C. Katwa, “PPAR-γ agonists induce the expression of VEGF and its receptors in cultured cardiac myofibroblasts,” Cardiovascular Research, vol. 74, no. 1, pp. 140–150, 2007.
[115]
D. H. Kim, J. H. Kim, E. H. Kim et al., “15-Deoxy-Δ12,14-prostaglandin J2 upregulates the expression of heme oxygenase-1 and subsequently matrix metalloproteinase-1 in human breast cancer cells: possible roles of iron and ROS,” Carcinogenesis, vol. 30, no. 4, pp. 645–654, 2009.
[116]
A. M. Lefebvre, I. Chen, P. Desreumaux et al., “Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-AP mice,” Nature Medicine, vol. 4, no. 9, pp. 1053–1057, 1998.
[117]
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.
[118]
R. Z. Karim, G. M. K. Tse, T. C. Putti, R. A. Scolyer, and C. S. Lee, “The significance of the Wnt pathway in the pathology of human cancers,” Pathology, vol. 36, no. 2, pp. 120–128, 2004.
[119]
D. Wang and R. N. Dubois, “Prostaglandins and cancer,” Gut, vol. 55, no. 1, pp. 115–122, 2006.
[120]
A. Józkowicz, I. Huk, A. Nigisch, J. Cisowski, G. Weigel, and J. Dulak, “Prostaglandin-J2 upregulates expression of matrix metalloproteinase-1 independently of activation of peroxisome proliferator-activated receptor-γ,” Acta Biochimica Polonica, vol. 50, no. 3, pp. 677–689, 2003.
[121]
F. Varnat, B. B. Heggeler, P. Grisel et al., “PPARβ/δ regulates paneth cell differentiation via controlling the hedgehog signaling pathway,” Gastroenterology, vol. 131, no. 2, pp. 538–553, 2006.
[122]
T. C. He, T. A. Chan, B. Vogelstein, and K. W. Kinzler, “PPARδ is an APC-regulated target of nonsteroidal anti-inflammatory drugs,” Cell, vol. 99, no. 3, pp. 335–345, 1999.
[123]
R. A. Gupta, J. Tan, W. F. Krause et al., “Prostacyclin-mediated activation of peroxisome proliferator-activated receptor δ in colorectal cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 24, pp. 13275–13280, 2000.
[124]
B. H. Park, B. Vogelstein, and K. W. Kinzler, “Genetic disruption of PPARδ decreases the tumorigenicity of human colon cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 5, pp. 2598–2603, 2001.
[125]
J. Shao, H. Sheng, and R. N. Dubois, “Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells,” Cancer Research, vol. 62, no. 11, pp. 3282–3288, 2002.
[126]
N. Di-Po？, N. S. Tan, L. Michalik, W. Wahli, and B. Desvergne, “Antiapoptotic role of PPARβ in keratinocytes via transcriptional control of the Akt1 signaling pathway,” Molecular Cell, vol. 10, no. 4, pp. 721–733, 2002.
[127]
D. Wang, H. Wang, Y. Guo et al., “Crosstalk between peroxisome proliferator-activated receptor δ and VEGF stimulates cancer progression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 50, pp. 19069–19074, 2006.
[128]
H. Kwak, I. Hwang, J. H. Kim, Y. K. Mee, J. S. Yang, and S. Jeong, “Modulation of transcription by the peroxisome proliferator-activated receptor δ-binding RNA aptamer in colon cancer cells,” Molecular Cancer Therapeutics, vol. 8, no. 9, pp. 2664–2673, 2009.
[129]
K. R. Reed, O. J. Sansom, A. J. Hayes et al., “PPARδ status and Apc-mediated tumourigenesis in the mouse intestine,” Oncogene, vol. 23, no. 55, pp. 8992–8996, 2004.
[130]
J. M. Peters and F. J. Gonzalez, “Sorting out the functional role(s) of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in cell proliferation and cancer,” Biochimica et Biophysica Acta, vol. 1796, no. 2, pp. 230–241, 2009.
[131]
J. M. Peters, H. E. Hollingshead, and F. J. Gonzalez, “Role of peroxisome-proliferator-activated receptor β/δ (PPARβ/δ) in gastrointestinal tract function and disease,” Clinical Science, vol. 115, no. 3-4, pp. 107–127, 2008.
[132]
K. Nadra, S. I. Anghel, E. Joye et al., “Differentiation of trophoblast giant cells and their metabolic functions are dependent on peroxisome proliferator-activated receptor β/δ,” Molecular and Cellular Biology, vol. 26, no. 8, pp. 3266–3281, 2006.
[133]
X. Zuo, Z. Peng, M. J. Moussalli et al., “Targeted genetic disruption of peroxisome proliferator-activated receptor-δ and colonic tumorigenesis,” Journal of the National Cancer Institute, vol. 101, no. 10, pp. 762–767, 2009.
[134]
F. S. Harman, C. J. Nicol, H. E. Marin, J. M. Ward, F. J. Gonzalez, and J. M. Peters, “Peroxisome proliferator-activated receptor-δ attenuates colon carcinogenesis,” Nature Medicine, vol. 10, no. 5, pp. 481–483, 2004.
[135]
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 β(δ),” Molecular and Cellular Biology, vol. 20, no. 14, pp. 5119–5128, 2000.
[136]
L. Kopelovich, Y. Yin, R. G. Russell et al., “Peroxisome proliferator-activator receptor δ and γ agonists differentially alter tumor differentiation and progression during mammary carcinogenesis,” Cancer Research, vol. 65, no. 9, pp. 3950–3957, 2005.
[137]
L. Yang, B. Olsson, D. Pfeifer et al., “Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell-fibronectin adhesion of colon cancer cells,” Oncogene, vol. 29, no. 4, pp. 516–526, 2010.
[138]
K. K. Wu and J. Y. Liou, “Cyclooxygenase inhibitors induce colon cancer cell apoptosis via PPARδ→14-3-3ε pathway,” Methods in Molecular Biology, vol. 512, pp. 295–307, 2009.
