Browse > Article

PPARγ Physiology and Pathology in Gastrointestinal Epithelial Cells  

Thompson, E. Aubrey (Mayo Clinic Comprehensive Cancer Center)
Publication Information
Molecules and Cells / v.24, no.2, 2007 , pp. 167-176 More about this Journal
Abstract
Peroxisome proliferator-activated receptor-gamma ($PPAR{\gamma}$) is expressed at very high levels in the gastrointestinal epithelium. Many of the functions of $PPAR{\gamma}$ in gastrointestinal epithelial cells have been elucidated in recent years, and a pattern is emerging which suggests that this receptor plays an important role in gastrointestinal physiology. There is also strong evidence that $PPAR{\gamma}$ is a colon cancer suppressor in pre-clinical rodent models of sporadic colon cancer, and there is considerable interest in exploitation of $PPAR{\gamma}$ agonists as prophylactic or chemopreventive agents in colon cancer. Studies in mice and in human colon cancer cell lines suggest several mechanisms that might account for the tumor suppressive effects of $PPAR{\gamma}$ agonists, although it is not in all cases clear whether these effects are altogether mediated by $PPAR{\gamma}$. Conversely, several reports suggest that $PPAR{\gamma}$ agonists may promote colon cancer under certain circumstances. This possibility warrants considerable attention since several million individuals with type II diabetes are currently taking $PPAR{\gamma}$ agonists. This review will focus on recent data related to four critical questions: what is the physiological function of $PPAR{\gamma}$ in gastrointestinal epithelial cells; how does $PPAR{\gamma}$ suppress colon carcinogenesis; is $PPAR{\gamma}$ a tumor promoter; and what is the future of $PPAR{\gamma}$ in colon cancer prevention?
Keywords
Colon Cancer; Gastroenterology; Gastrointestinal Epithelial Cells; Peroxisome Proliferator-activated Receptor Gamma; Thiazolidinedione;
Citations & Related Records

Times Cited By Web Of Science : 25  (Related Records In Web of Science)
연도 인용수 순위
  • Reference
1 Bogazzi, F., Ultimieri, F., Raggi, F., Costa, A., Gasperi, M., et al. (2002) Peroxisome proliferator activated receptor gamma expression is reduced in the colonic mucosa of acromegalic patients. J. Clin. Endocrinol. Metab. 87, 2403−2406
2 Chen, L., Necela, B. M., Su, W., Yanagisawa, M., Anastasiadis, P. Z., et al. (2006b) Peroxisome proliferator-activated receptor gamma promotes epithelial to mesenchymal transformation by Rho GTPase-dependent activation of ERK1/2. Chen, L., Necela, B. M., Su, W., Yanagisawa, M., Anastasiadis, P. Z., et al. (2006b) Peroxisome proliferator-activated receptor gamma promotes epithelial to mesenchymal transformation by Rho GTPase-dependent activation of ERK1/2. J. Biol. Chem. 281, 24575−24587
3 Dubuquoy, L., Rousseaux, C., Thuru, X., Peyrin-Biroulet, L., Romano, O., et al. (2006) PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut 55, 1341−1349
4 Fajas, L., Fruchart, J. C., and Auwerx, J. (1998) PPARgamma3 mRNA: a distinct PPARgamma mRNA subtype transcribed from an independent promoter. FEBS Lett. 438, 55−60
5 Fujiwara, T., Wada, M., Fukuda, K., Fukami, M., Yoshioka, S., et al. (1991) Characterization of CS-045, a new oral antidiabetic agent, II. effects on glycemic control and pancreatic islet structure at a late stage of the diabetic syndrome in C57BL/KsJ-db/db mice. Metabolism 40, 1213−1218
6 Hu, E., Tontonoz, P., and Spiegelman, B. M. (1995) Transdifferentiation of myoblasts by the adipogenic transcription factors PPAR gamma and C/EBP alpha. Proc. Natl. Acad. Sci USA 92, 9856−9860
7 Kitamura, S., Miyazaki, Y., Shinomura, Y., Kondo, S., Kanayama, S., et al. (1999) Peroxisome proliferator-activated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells. Jpn. J. Cancer Res. 90, 75−80
8 Kubota, T., Koshizuka, K., Williamson, E. A., Asou, H., Said, J. W., et al. (1998) Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res. 58, 3344−3352
9 Laidler, P., Dulinska, J., and Mrozicki, S. (2007) Does the inhibition of c-myc expression mediate the anti-tumor activity of PPAR's ligands in prostate cancer cell lines? Arch. Biochem. Biophys. 462, 1−12
10 Lefebvre, M., Paulweber, B., Fajas, L., Woods, J., McCrary, C., et al. (1999) Peroxisome proliferator-activated receptor gamma is induced during differentiation of colon epithelium cells. J. Endocrinol. 162, 331−340
11 McAlpine, C. A., Barak, Y., Matise, I., and Cormier, R. T. (2006) Intestinal-specific PPARgamma deficiency enhances tumorigenesis in ApcMin/+ mice. Int. J. Cancer 119, 2339− 2346
12 Niho, N., Takahashi, M., Shoji, Y., Takeuchi, Y., Matsubara, S., et al. (2003b) Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPAR gamma ligand. Cancer Sci. 94, 960−964
13 Nolte, R. T., Wisely, G. B., Westin, S., Cobb, J. E., Lambert, M. H., et al. (1998) Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395, 137−143
14 Osawa, E., Nakajima, A., Wada, K., Ishimine, S., Fujisawa, N., et al. (2003) Peroxisome proliferator-activated receptor gamma ligands suppress colon carcinogenesis induced by azoxymethane in mice. Gastroenterology 124, 361−367
15 Saez, E., Tontonoz, P., Nelson, M. C., Alvarez, J. G., Ming, U. T., et al. (1998) Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat. Med. 4, 1058−1061
16 Sanchez-Hidalgo, M., Martin, A. R., Villegas, I., and de la Lastra, C. A. (2007) Rosiglitazone, a PPARgamma ligand, modulates signal transduction pathways during the development of acute TNBS-induced colitis in rats. Eur. J. Pharmacol. 562, 247−258
17 Sarraf, P., Mueller, E., Jones, D., King, F. J., DeAngelo, D. J., et al. (1998) Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat. Med. 4, 1046−1052
18 Simoncini, T., Scorticati, C., Mannella, P., Fadiel, A., Giretti, M. S., et al. (2006) Estrogen receptor alpha interacts with Galpha13 to drive actin remodeling and endothelial cell migration via the RhoA/Rho kinase/moesin pathway. Mol. Endocrinol. 20, 1756−71
19 Takayama, T., Katsuki, S., Takahashi, Y., Ohi, M., Nojiri, S., et al. (1998) Aberrant crypt foci of the colon as precursors of adenoma and cancer. N. Engl. J. Med. 339, 1277−1284
20 Tontonoz, P., Hu, E., Graves, R. A., Budavari, A. I., and Spiegelman, B. M. (1994a) mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 8, 1224−1234
21 Tontonoz, P., Hu, E., Devine, J., Beale, E. G., and Spiegelman, B. M. (1995) PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Mol. Cell. Biol. 15, 351−357
22 Wang, M., Wise, S. C., Leff, T., and Su, T. Z. (1999) Troglitazone, an antidiabetic agent, inhibits cholesterol biosynthesis through a mechanism independent of peroxisome proliferator- activated receptor-gamma. Diabetes 48, 254−260
23 Yamazaki, K., Shimizu, M., Okuno, M., Matsushima-Nishiwaki, R., Kanemura, N., et al. (2007) Synergistic effects of RXR {alpha} and PPAR{gamma} ligands to inhibit growth in human colon cancer cells - phosphorylated RXR{alpha} is a critical target for colon cancer management 1. Gut [Epub ahead of print]
24 Yoshizumi, T., Ohta, T., Ninomiya, I., Terada, I., Fushida, S., et al. (2004) Thiazolidinedione, a peroxisome proliferatoractivated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation- promoting effects. Int. J. Oncol. 25, 631−639
25 Zhu, Y., Alvares, K., Huang, Q., Rao, M. S., and Reddy, J. K. (1993) Cloning of a new member of the peroxisome proliferator- activated receptor gene family from mouse liver. J. Biol. Chem. 268, 26817−26820
26 Shimada, T., Kojima, K., Yoshiura, K., Hiraishi, H., and Terano, A. (2002) Characteristics of the peroxisome proliferator activated receptor gamma (PPARgamma) ligand induced apoptosis in colon cancer cells. Gut 50, 658−664
27 Su, W., Bush, C. R., Necela, B., Calcagno, S. R., Murray, N. R., et al. (2007) Differential expression, distribution, and function of PPAR-gamma in the proximal and distal colon. Physiol. Genomics 30, 342−353
28 Yokota, T., Sugano, K., Kondo, H., Saito, D., Sugihara, K., et al. (1997) Detection of aberrant crypt foci by magnifying colonoscopy. Gastrointest. Endosc. 46, 61−65
29 Ikezoe, T., Miller, C. W., Kawano, S., Heaney, A., Williamson, E. A., et al. (2001) Mutational analysis of the peroxisome proliferator-activated receptor gamma gene in human malignancies. Cancer Res. 61, 5307−5310
30 Nissen, S. E. and Wolski, K. (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457−2471
31 Baek, S. J., Wilson, L. C., Hsi, L. C., and Eling, T. E. (2003) Troglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, selectively induces the early growth response-1 gene independently of PPARgamma. A novel mechanism for its anti-tumorigenic activity. J. Biol. Chem. 278, 5845− 5853
32 Forman, B. M., Chen, J., and Evans, R. M. (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc. Natl. Acad. Sci USA 94, 4312−4317
33 Iankova, I., Petersen, R. K., Annicotte, J. S., Chavey, C., Hansen, J. B., et al. (2006) Peroxisome proliferator-activated receptor gamma recruits the positive transcription elongation factor b complex to activate transcription and promote adipogenesis. Mol. Endocrinol. 20, 1494−1505
34 Matthiessen, M. W., Pedersen, G., Albrektsen, T., Adamsen, S., Fleckner, J., et al. (2005) Peroxisome proliferator-activated receptor expression and activation in normal human colonic epithelial cells and tubular adenomas. Scand J. Gastroenterol. 40, 198−205
35 Niho, N., Takahashi, M., Kitamura, T., Shoji, Y., Itoh, M., et al. (2003a) Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands. Cancer Res. 63, 6090−6095
36 Yang, K., Fan, K. H., Lamprecht, S. A., Edelmann, W., Kopelovich, L., et al. (2005) Peroxisome proliferator-activated receptor gamma agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in Apc1638 N/+ Mlh1+/- double mutant mice. Int. J. Cancer 116, 495−499
37 Girnun, G. D., Smith, W. M., Drori, S., Sarraf, P., Mueller, E., et al. (2002) APC-dependent suppression of colon carcinogenesis by PPARgamma. Proc. Natl. Acad. Sci USA 99, 13771− 13776
38 Yamakawa-Karakida, N., Sugita, K., Inukai, T., Goi, K., Nakamura, M., et al. (2002) Ligand activation of peroxisome proliferator- activated receptor gamma induces apoptosis of leukemia cells by down-regulating the c-myc gene expression via blockade of the Tcf-4 activity. Cell Death Differ. 9, 513−526
39 Cerbone, A., Toaldo, C., Laurora, S., Briatore, F., Pizzimenti, S., et al. (2007) 4-Hydroxynonenal and PPARgamma ligands affect proliferation, differentiation, and apoptosis in colon cancer cells. Free Radic. Biol. Med. 42, 1661−1670
40 Gupta, R. A., Sarraf, P., Mueller, E., Brockman, J. A., Prusakiewicz, J. J., et al. (2003b) Peroxisome proliferatoractivated receptor gamma-mediated differentiation: a mutation in colon cancer cells reveals divergent and cell typespecific mechanisms. J. Biol. Chem. 278, 22669−22677
41 Shirasawa, S., Furuse, M., Yokoyama, N., and Sasazuki, T. (1993) Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260, 85−88
42 Tontonoz, P., Hu, E., and Spiegelman, B. M. (1994b) Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79, 1147−1156
43 Cesario, R. M., Stone, J., Yen, W. C., Bissonnette, R. P., and Lamph, W. W. (2006) Differentiation and growth inhibition mediated via the RXR:PPARgamma heterodimer in colon cancer. Cancer Lett. 240, 225−233
44 Fajas, L., Auboeuf, D., Raspe, E., Schoonjans, K., Lefebvre, A. M., et al. (1997) The organization, promoter analysis, and expression of the human PPARgamma gene. J. Biol. Chem. 272, 18779−18789
45 Kato, M., Kusumi, T., Tsuchida, S., Tanaka, M., Sasaki, M., et al. (2004) Induction of differentiation and peroxisome proliferator- activated receptor gamma expression in colon cancer cell lines by troglitazone. J. Cancer Res. Clin. Oncol. 130, 73− 79
46 Chen, L., Bush, C. R., Necela, B. M., Su, W., Yanagisawa, M., et al. (2006a) RS5444, a novel PPARgamma agonist, regulates aspects of the differentiated phenotype in nontransformed intestinal epithelial cells. Mol. Cell. Endocrinol. 251, 17−32
47 Kulke, M. H., Demetri, G. D., Sharpless, N. E., Ryan, D. P., Shivdasani, R., et al. (2002) A phase II study of troglitazone, an activator of the PPARgamma receptor, in patients with chemotherapy-resistant metastatic colorectal cancer. Cancer J. 8, 395−399
48 Demetri, G. D., Fletcher, C. D., Mueller, E., Sarraf, P., Naujoks, R., et al. (1999) Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma. Proc. Natl. Acad. Sci USA 96, 3951−3956
49 Gupta, R. A., Sarraf, P., Brockman, J. A., Shappell, S. B., Raftery, L. A., et al. (2003a) Peroxisome proliferator-activated receptor gamma and transforming growth factor-beta pathways inhibit intestinal epithelial cell growth by regulating levels of TSC-22. J. Biol. Chem. 278, 7431−7438
50 Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M., et al. (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferatoractivated receptor gamma (PPAR gamma). J. Biol. Chem. 270, 12953−12956
51 Brockman, J. A., Gupta, R. A., and Dubois, R. N. (1998) Activation of PPARgamma leads to inhibition of anchorageindependent growth of human colorectal cancer cells. Gastroenterology 115, 1049−1055   DOI
52 Drori, S., Girnun, G. D., Tou, L., Szwaya, J. D., Mueller, E., et al. (2005) Hic-5 regulates an epithelial program mediated by PPARgamma. Genes Dev. 19, 362−375
53 Schoonjans, K., Peinado-Onsurbe, J., Lefebvre, A. M., Heyman, R. A., Briggs, M., et al. (1996) PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 15, 5336−5348
54 Adler, D. G., Gostout, C. J., Sorbi, D., Burgart, L. J., Wang, L., et al. (2002) Endoscopic identification and quantification of aberrant crypt foci in the human colon. Gastrointest. Endosc. 56, 657−662
55 Bush, C. R., Havens, J. M., Necela, B. M., Su, W., Chen, L., et al. (2007) Functional genomic analysis reveals cross-talk between peroxisome proliferator-activated receptor gamma and calcium signaling in human colorectal cancer cells. J. Biol. Chem. 282, 23387−23401
56 Chen, G. G., Lee, J. F., Wang, S. H., Chan, U. P., Ip, P. C., et al. (2002) Apoptosis induced by activation of peroxisomeproliferator activated receptor-gamma is associated with Bcl- 2 and NF-kappaB in human colon cancer. Life Sci. 70, 2631− 2646
57 Kohno, H., Yoshitani, S., Takashima, S., Okumura, A., Hosokawa, M., et al. (2001) Troglitazone, a ligand for peroxisome proliferator-activated receptor gamma, inhibits chemicallyinduced aberrant crypt foci in rats. Jpn. J. Cancer Res. 92, 396−403
58 Sarraf, P., Mueller, E., Smith, W. M., Wright, H. M., Kum, J. B., et al. (1999) Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol. Cell 3, 799− 804
59 Xu, H. E., Lambert, M. H., Montana, V. G., Parks, D. J., Blanchard, S. G., et al. (1999) Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell 3, 397−403
60 Uppenberg, J., Svensson, C., Jaki, M., Bertilsson, G., Jendeberg, L., et al. (1998) Crystal structure of the ligand binding domain of the human nuclear receptor PPARgamma. J. Biol. Chem. 273, 31108−31112
61 Burstein, H. J., Demetri, G. D., Mueller, E., Sarraf, P., Spiegelman, B. M., et al. (2003) Use of the peroxisome proliferatoractivated receptor (PPAR) gamma ligand troglitazone as treatment for refractory breast cancer: a phase II study. Breast Cancer Res. Treat. 79, 391−397
62 Shah, Y. M., Morimura, K., and Gonzalez, F. J. (2007) Expression of peroxisome proliferator-activated receptor-gamma in macrophage suppresses experimentally induced colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G657−666
63 Zhu, X., Lin, Y., Zhang, J., Fu, M., Mao, Z., et al. (2003) Thiazolidinediones, a class of anti-diabetic drugs, inhibit Id2 expression through a PPARgamma-independent pathway in human aortic smooth muscle cells. Cell. Mol. Life Sci. 60, 212−218
64 Mueller, E., Sarraf, P., Tontonoz, P., Evans, R. M., Martin, K. J., et al. (1998) Terminal differentiation of human breast cancer through PPAR gamma. Mol. Cell 1, 465−470
65 Brunmair, B., Gras, F., Neschen, S., Roden, M., Wagner, L., et al. (2001) Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-{gamma}-mediated changes in gene expression. Diabetes 50, 2309−2315
66 Copland, J. A., Marlow, L. A., Kurakata, S., Fujiwara, K., Wong, A. K., et al. (2006) Novel high-affinity PPARgamma agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/ CIP1. Oncogene 25, 2304−2317
67 Mukherjee, R., Jow, L., Croston, G. E., and Paterniti, J. R., Jr. (1997) Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J. Biol. Chem. 272, 8071−8076
68 Tanaka, T., Kohno, H., Yoshitani, S., Takashima, S., Okumura, A., et al. (2001) Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemically induced colitis and formation of aberrant crypt foci in rats. Cancer Res. 61, 2424−2428
69 Lefebvre, A. M., Chen, I., Desreumaux, P., Najib, J., Fruchart, J. C., et al. (1998) Activation of the peroxisome proliferatoractivated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat. Med. 4, 1053− 1057