Nowadays, the study of the peroxisome proliferators activated receptors (PPARs) as potential targets for cancer prevention and therapy has gained a strong interest. From a biological point of view, the overall responsibility of PPARs in cancer development and progression is still controversial since several studies report both antiproliferative and tumor-promoting actions for these signaling molecules in human cancer cells and animal models. In this paper, we discuss PPARs functions in the context of different types of gastrointestinal cancer. 1. Introduction Since the discovery of the peroxisome proliferators activated receptors (PPARs) [1] in Xenopus frogs as receptors that induce the proliferation of peroxisomes in cells [2], three main forms transcribed from three different genes have been indentified: PPARα, PPARβ/δ, and PPARγ. Despite the little divergence of homology observed, each isoform possesses distinct biological activities and is expressed in different tissues [3]. PPARα is mainly expressed in the liver, the kidney, and the heart and is primarily involved in lipid metabolism. PPARγ is a master regulator of adipogenesis and fat storage: it regulates adipocyte differentiation and insulin sensitivity in adipose tissue. PPARβ/δ is found in a broad range of tissues but markedly expressed in brain, adipose tissue, and skin and its function awaits further exploration. PPARs are key mediators of energy homeostasis, lipid, and glucose metabolism although they have also been associated with other biological processes including development, differentiation, inflammation, atherosclerosis, wound healing, and tumor formation. All PPARs heterodimerize with the retinoid X receptor (RXR) to bind successively to specific DNA regions of target genes named PPREs (peroxisome proliferator hormone response elements). Like PPARs, RXR exists as three distinct isoforms: RXRα, β, and γ, all of which are activated by the endogenous agonist 9-cis retinoic acid [4]. Contrasting observations confer to PPARs a double-edge sword nature in cancerogenesis, considering that either tumor suppressing or stimulating effects have been evidenced for these nuclear receptors [5]. PPARs function is modified by the specific shape of their ligand-binding domain induced by ligand binding and by a number of coactivator and corepressor proteins, the presence of which can stimulate or inhibit receptor function, respectively [6]. Endogenous ligands for the PPARs include free fatty acids and eicosanoids. PPAR isoform-specific agonists, specifically fibrates for PPARα and thiazolidinediones
References
[1]
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.
[2]
C. Dreyer, G. Krey, H. Keller, F. Givel, G. Helftenbein, and W. Wahli, “Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors,” Cell, vol. 68, no. 5, pp. 879–887, 1992.
[3]
P. Escher and W. Wahli, “Peroxisome proliferator-activated receptors: Insight into multiple cellular functions,” Mutation Research, vol. 448, no. 2, pp. 121–138, 2000.
[4]
D. J. Mangelsdorf, U. Borgmeyer, R. A. Heyman et al., “Characterization of three RXR genes that mediate the action of 9-cis retinoic acid,” Genes and Development, vol. 6, no. 3, pp. 329–344, 1992.
[5]
D. Panigrahy, A. Kaipainen, M. W. Kieran, and S. Huang, “PPARs: a double-edged sword in cancer yherapy?” PPAR Research, vol. 2008, Article ID 350351, 2 pages, 2008.
[6]
S. Yu and J. K. Reddy, “Transcription coactivators for peroxisome proliferator-activated receptors,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 936–951, 2007.
[7]
W. Xu and P. Charoensuksai, “PPARs in rhythmic metabolic regulation and implications in health and disease,” PPAR Research, vol. 2010, Article ID 243643, 9 pages, 2010.
[8]
G. Eibl, “The role of PPAR-γ and its interaction with COX-2 in pancreatic cancer,” PPAR Research, vol. 2008, Article ID 326915, 6 pages, 2008.
[9]
K. Yang, K. H. Fan, S. A. Lamprecht et al., “Peroxisome proliferator-activated receptor γ agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in Apc1638 N/+ Mlh1+/？ double mutant mice,” International Journal of Cancer, vol. 116, no. 4, pp. 495–499, 2005.
[10]
M. V. Pino, M. F. Kelley, and Z. Jayyosi, “Promotion of colon tumors in C57BL/6J-APCmin/+ mice by thiazolidinedione PPARγ agonists and a structurally unrelated PPARγ agonist,” Toxicologic Pathology, vol. 32, no. 1, pp. 58–63, 2004.
[11]
I. A. Voutsadakis, “Peroxisome proliferator-activated receptor γ (PPARγ) and colorectal carcinogenesis,” Journal of Cancer Research and Clinical Oncology, vol. 133, no. 12, pp. 917–928, 2007.
[12]
J. Bassaganya-Riera, A. B. Carter, S. A. Misyak, and R. Hontecillas, “Dietary modulation of inflammation-induced colorectal cancer through PPARγ,” PPAR Research, vol. 2009, Article ID 498352, 9 pages, 2009.
[13]
J. M. Peters, Y. M. Shah, and F. J. Gonzalez, “The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention,” Nature Reviews Cancer, vol. 12, no. 3, pp. 181–195, 2012.
[14]
G. T. Robbins and D. Nie, “PPAR gamma, bioactive lipids, and cancer progression,” Frontiers in Bioscience, vol. 17, pp. 1816–1834, 2012.
[15]
Y. L. Lu, G. L. Li, H. L. Huang, J. Zhong, and L. C. Dai, “Peroxisome proliferator-activated receptor-γ 34C>G polymorphism and colorectal cancer risk: a meta-analysis,” World Journal of Gastroenterology, vol. 16, no. 17, pp. 2170–2175, 2010.
[16]
D. Capaccio, A. Ciccodicola, L. Sabatino et al., “A novel germline mutation in peroxisome proliferator-activated receptor γ gene associated with large intestine polyp formation and dyslipidemia,” Biochimica et Biophysica Acta, vol. 1802, no. 6, pp. 572–581, 2010.
[17]
Y. Dai, L. Qiao, W. C. Kwok et al., “Peroxisome proliferator-activated receptor-γ contributes to the inhibitory effects of embelin on colon carcinogenesis,” Cancer Research, vol. 69, no. 11, pp. 4776–4783, 2009.
[18]
L. Qiao, B. Zou, and B. C. Y. Wong, “Current understanding of the role of PPAR γ in gastrointestinal cancers,” PPAR Research, vol. 2009, Article ID 816957, 8 pages, 2009.
[19]
G. D. Girnun, W. M. Smith, S. Drori et al., “APC-dependent suppression of colon carcinogenesis by PPARγ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 21, pp. 13771–13776, 2002.
[20]
W. Wang, R. Wang, Z. Zhang, D. Li, and Y. Yu, “Enhanced PPAR-γ expression may correlate with the development of Barrett's esophagus and esophageal adenocarcinoma,” Oncology Research, vol. 19, no. 3-4, pp. 141–147, 2011.
[21]
X. M. Ma, H. Yu, and N. Huai, “Peroxisome proliferator-activated receptor-γ is essential in the pathogenesis of gastric carcinoma,” World Journal of Gastroenterology, vol. 15, no. 31, pp. 3874–3883, 2009.
[22]
L. Yao, F. Liu, L. Sun et al., “Upregulation of PPARγ in tissue with gastric carcinoma,” Hybridoma, vol. 29, no. 4, pp. 341–343, 2010.
[23]
H. Sato, S. Ishihara, K. Kawashima et al., “Expression of peroxisome proliferator-activated receptor (PPAR)γ in gastric cancer and inhibitory effects of PPARγ agonists,” British Journal of Cancer, vol. 83, no. 10, pp. 1394–1400, 2000.
[24]
Y. Dai and W. H. Wang, “Peroxisome proliferator-activated receptor γ and colorectal cancer,” The World Journal of Gastrointestinal Oncology, vol. 2, no. 3, pp. 159–164, 2010.
[25]
P. A. Konstantinopoulos, G. P. Vandoros, G. Sotiropoulou-Bonikou, A. Kominea, and A. G. Papavassiliou, “NF-κB/PPARγ and/or AP-1/PPARγ ‘on/off' switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression,” International Journal of Colorectal Disease, vol. 22, no. 1, pp. 57–68, 2007.
[26]
M. Pancione, L. Sabatino, A. Fucci et al., “Epigenetic silencing of peroxisome proliferator- activated receptor γ is a biomarker for colorectal cancer progression and adverse patients' outcome,” PLoS One, vol. 5, no. 12, Article ID e14229, 2010.
[27]
L. Sabatino, A. Fucci, M. Pancione et al., “UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression,” Oncogene. In press.
[28]
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.
[29]
A. Papi, P. Rocchi, A. M. Ferreri, and M. Orlandi, “RXRγ and PPARγ ligands in combination to inhibit proliferation and invasiveness in colon cancer cells,” Cancer Letters, vol. 297, no. 1, pp. 65–74, 2010.
[30]
T. Tsukahara, S. Hanazawa, T. Kobayashi, Y. Iwamoto, and K. Murakami-Murofushi, “Cyclic phosphatidic acid decreases proliferation and survival of colon cancer cells by inhibiting peroxisome proliferator-activated receptor γ,” Prostaglandins and Other Lipid Mediators, vol. 93, no. 3-4, pp. 126–133, 2010.
[31]
C. R？hrl, U. Kaindl, I. Koneczny et al., “Peroxisome-proliferator-activated receptors γ and β/δ mediate vascular endothelial growth factor production in colorectal tumor cells,” Journal of Cancer Research and Clinical Oncology, vol. 137, no. 1, pp. 29–39, 2011.
[32]
J. M. Peters, J. E. Foreman, and F. J. Gonzalez, “Dissecting the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in colon, breast, and lung carcinogenesis,” Cancer and Metastasis Reviews, vol. 30, no. 3-4, pp. 619–640, 2011.
[33]
J. E. Foreman, W. C. L. Chang, P. S. Palkar et al., “Functional characterization of peroxisome proliferator-activated receptor-β/δ expression in colon cancer,” Molecular Carcinogenesis, vol. 50, no. 11, pp. 884–900, 2011.
[34]
L. Yang, H. Zhang, Z. G. Zhou, H. Yan, G. Adell, and X. F. Sun, “Biological function and prognostic significance of peroxisome proliferator-activated receptor δ in rectal cancer,” Clinical Cancer Research, vol. 17, no. 11, pp. 3760–3770, 2011.
[35]
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.
[36]
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.
[37]
M. Yoshinaga, K. Taki, S. Somada et al., “The expression of both peroxisome proliferator-activated receptor delta and cyclooxygenase-2 in tissues is associated with poor prognosis in colorectal cancer patients,” Digestive Diseases and Sciences, vol. 56, no. 4, pp. 1194–1200, 2011.
[38]
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.
[39]
M. Ripoli and V. Pazienza, “Impact of HCV genetic differences on pathobiology of disease,” Expert Review of Anti-Infective Therapy, vol. 9, no. 9, pp. 747–759, 2011.
[40]
M. Romero-Gómez, M. Del Mar Viloria, R. J. Andrade et al., “Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients,” Gastroenterology, vol. 128, no. 3, pp. 636–641, 2005.
[41]
V. Pazienza, M. Vinciguerra, A. Andriulli, and A. Mangia, “Hepatitis C virus core protein genotype 3a increases SOCS-7 expression through PPAR-γ in Huh-7 cells,” Journal of General Virology, vol. 91, no. 7, pp. 1678–1686, 2010.
[42]
S. Dharancy, M. Lemoine, P. Mathurin, L. Serfaty, and L. Dubuquoy, “Peroxisome proliferator-activated receptors in HCV-related infection,” PPAR Research, vol. 2009, Article ID 357204, 5 pages, 2009.
[43]
M. Tsujie, S. Nakamori, J. Okami et al., “Thiazolidinediones inhibit growth of gastrointestinal, biliary, and pancreatic adenocarcinoma cells through activation of the peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha pathway,” Experimental Cell Research, vol. 289, no. 1, pp. 143–151, 2003.
[44]
H. Yu and R. Jove, “The stats of cancer—new molecular targets come of age,” Nature Reviews Cancer, vol. 4, no. 2, pp. 97–105, 2004.
[45]
V. Pazienza, F. Tavano, G. Benegiamo et al., “Correlations among PPARγ, DNMT1, and DNMT3B expression levels and pancreatic cancer,” PPAR Research, vol. 2012, Article ID 461784, 7 pages, 2012.
[46]
A. D. Patterson, O. Maurhofer, D. Beyoglu et al., “Aberrant lipid metabolism in hepatocellular carcinoma revealed by plasma metabolomics and lipid profiling,” Cancer Research, vol. 71, no. 21, pp. 6590–6600, 2011.
[47]
M. Vacca, C. Degirolamo, R. Mariani-Costantini, G. Palasciano, and A. Moschetta, “Lipid-sensing nuclear receptors in the pathophysiology and treatment of the metabolic syndrome,” Wiley Interdisciplinary Reviews: Systems Biology and Medicine, vol. 3, no. 5, pp. 562–587, 2011.
[48]
G. Li and G. L. Guo, “Role of class II nuclear receptors in liver carcinogenesis,” Anti-Cancer Agents in Medicinal Chemistry, vol. 11, no. 6, pp. 529–542, 2011.
[49]
K. Matsusue, T. Kusakabe, T. Noguchi et al., “Hepatic steatosis in leptin-deficient mice is promoted by the PPARγ target gene Fsp27,” Cell Metabolism, vol. 7, no. 4, pp. 302–311, 2008.
[50]
D. L. M. van der Meer, T. Degenhardt, S. V？is？nen et al., “Profiling of promoter occupancy by PPARα in human hepatoma cells via ChIP-chip analysis,” Nucleic Acids Research, vol. 38, no. 9, Article ID gkq012, pp. 2839–2850, 2010.
[51]
K. Z. Guyton, W. A. Chiu, T. F. Bateson et al., “A reexamination of the PPAR-α activation mode of action as a basis for assessing human cancer risks of environmental contaminants,” Environmental Health Perspectives, vol. 117, no. 11, pp. 1664–1672, 2009.
[52]
J. C. Corton, “Evaluation of the role of peroxisome proliferator-activated receptor α (PPARα in mouse liver tumor induction by trichloroethylene and metabolites,” Critical Reviews in Toxicology, vol. 38, no. 10, pp. 857–875, 2008.
[53]
N. Tanaka, K. Moriya, K. Kiyosawa, K. Koike, F. J. Gonzalez, and T. Aoyama, “PPARα activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice,” Journal of Clinical Investigation, vol. 118, no. 2, pp. 683–694, 2008.
[54]
N. Tanaka, K. Moriya, K. Kiyosawa, K. Koike, and T. Aoyama, “Hepatitis C virus core protein induces spontaneous and persistent activation of peroxisome proliferator-activated receptor α in transgenic mice: Implications for HCV-associated hepatocarcinogenesis,” International Journal of Cancer, vol. 122, no. 1, pp. 124–131, 2008.
[55]
M. Maggiora, M. Oraldi, G. Muzio, and R. A. Canuto, “Involvement of PPARα and PPARγ in apoptosis and proliferation of human hepatocarcinoma HepG2 cells,” Cell Biochemistry and Function, vol. 28, no. 7, pp. 571–577, 2010.
[56]
J. Yu, B. Shen, E. S. H. Chu et al., “Inhibitory role of peroxisome proliferator-activated receptor gamma in hepatocarcinogenesis in mice and in vitro,” Hepatology, vol. 51, no. 6, pp. 2008–2019, 2010.
[57]
Y. M. Zhou, Y. H. Wen, X. Y. Kang, H. H. Qian, J. M. Yang, and Z. F. Yin, “Troglitazone, a peroxisome proliferator-activated receptor γ ligand, induces growth inhibition and apoptosis of HepG2 human liver cancer cells,” World Journal of Gastroenterology, vol. 14, no. 14, pp. 2168–2173, 2008.
[58]
Y. Yamamoto, T. Ono, D. K. Dhar et al., “Role of peroxisome proliferator-activated receptor-gamma (PPARγ) during liver regeneration in rats,” Journal of Gastroenterology and Hepatology, vol. 23, no. 6, pp. 930–937, 2008.
[59]
N. MartíNez-LóPez, M. Varela-Rey, D. FernáNdez-Ramos et al., “Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis,” Hepatology, vol. 52, no. 5, pp. 1621–1631, 2010.
[60]
D. Vara, M. Salazar, N. Olea-Herrero, M. Guzmán, G. Velasco, and I. Díaz-Laviada, “Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy,” Cell Death and Differentiation, vol. 18, no. 7, pp. 1099–1111, 2011.
[61]
K. Bhalla, B. J. Hwang, R. E. Dewi et al., “Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis,” Cancer Prevention Research, vol. 5, no. 4, pp. 544–552, 2012.
[62]
M. S. Sozio, C. Lu, Y. Zeng, S. Liangpunsakul, and D. W. Crabb, “Activated AMPK inhibits PPAR-α and PPAR-γ transcriptional activity in hepatoma cells,” American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 301, no. 4, pp. G739–G747, 2011.
[63]
K. M. Mueller, J. W. Kornfeld, K. Friedbichler et al., “Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice,” Hepatology, vol. 54, no. 4, pp. 1398–1409, 2011.
[64]
F. T. Wunderlich, T. Luedde, S. Singer et al., “Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 4, pp. 1297–1302, 2008.
[65]
J. Shim, B. H. Kim, Y. I. Kim et al., “The peroxisome proliferator-activated receptor γ ligands, pioglitazone and 15-deoxy-Δ12,14-prostaglandin J2, have antineoplastic effects against hepatitis B virus-associated hepatocellular carcinoma cells,” International Journal of Oncology, vol. 36, no. 1, pp. 223–231, 2010.
[66]
D. Yamasaki, N. Kawabe, H. Nakamura et al., “Fenofibrate suppresses growth of the human hepatocellular carcinoma cell via PPARα-independent mechanisms,” European Journal of Cell Biology, vol. 90, no. 8, pp. 657–664, 2011.
[67]
A. Galli, E. Ceni, T. Mello et al., “Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor γ-independent regulation of nucleophosmin,” Hepatology, vol. 52, no. 2, pp. 493–505, 2010.
[68]
I. Saito, T. Miyamura, A. Ohbayashi et al., “Hepatitis C virus infection is associated with the development of hepatocellular carcinoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 17, pp. 6547–6549, 1990.
[69]
S. Dharancy, M. Lemoine, P. Mathurin, L. Serfaty, and L. Dubuquoy, “Peroxisome proliferator-activated receptors in HCV-related infection,” PPAR Research, vol. 2009, Article ID 357204, 5 pages, 2009.
[70]
Y. Cheng, S. Dharancy, M. Malapel, and P. Desreumaux, “Hepatitis C virus infection down-regulates the expression of peroxisome proliferator-activated receptor α and carnitine palmitoyl acyl-CoA transferase 1A,” World Journal of Gastroenterology, vol. 11, no. 48, pp. 7591–7596, 2005.
[71]
S. Dharancy, M. Malapel, G. Perlemuter et al., “Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection,” Gastroenterology, vol. 128, no. 2, pp. 334–342, 2005.
[72]
A. De Gottardi, V. Pazienza, P. Pugnale et al., “Peroxisome proliferator-activated receptor-α and -γ mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection,” Alimentary Pharmacology and Therapeutics, vol. 23, no. 1, pp. 107–114, 2006.
[73]
V. Pazienza, S. Clément, P. Pugnale et al., “The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms,” Hepatology, vol. 45, no. 5, pp. 1164–1171, 2007.
[74]
H. M. Elgouhari, K. B. Cesario, R. Lopez, and N. N. Zein, “Pioglitazone improves early virologic kinetic response to PEG IFN/RBV combination therapy in hepatitis C genotype 1 naive pts,” Hepatology, vol. 48, article 383, 2008.
[75]
K. Overbeck, D. Genné, A. Golay, and F. Negro, “Pioglitazone in chronic hepatitis C not responding to pegylated interferon-α and ribavirin,” Journal of Hepatology, vol. 49, no. 2, pp. 295–298, 2008.
[76]
F. Negro, “Correction of insulin resistance in chronic hepatitis C patients not responding to the standard of care: more questions than answers,” Journal of Hepatology, vol. 50, no. 6, pp. 1271–1272, 2009.
[77]
K. H. Kim, H. J. Shin, K. Kim et al., “Hepatitis B Virus X Protein Induces Hepatic Steatosis Via Transcriptional Activation of SREBP1 and PPARγ,” Gastroenterology, vol. 132, no. 5, pp. 1955–1967, 2007.
[78]
L. G. Guidotti, C. M. Eggers, A. K. Raney et al., “In vivo regulation of hepatitis B virus replication by peroxisome proliferators,” Journal of Virology, vol. 73, no. 12, pp. 10377–10386, 1999.
[79]
Y. Wakui, J. Inoue, Y. Ueno et al., “Inhibitory effect on hepatitis B virus in vitro by a peroxisome proliferator-activated receptor-β ligand, rosiglitazone,” Biochemical and Biophysical Research Communications, vol. 396, no. 2, pp. 508–514, 2010.
[80]
A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer Journal for Clinicians, vol. 59, no. 4, pp. 225–249, 2009.
[81]
G. Kristiansen, J. Jacob, A. C. Buckendahl et al., “Peroxisome proliferator-activated receptor γ is highly expressed in pancreatic cancer and is associated with shorter overall survival times,” Clinical Cancer Research, vol. 12, no. 21, pp. 6444–6451, 2006.
[82]
K. Hashimoto, B. J. Farrow, and B. M. Evers, “Activation and Role of MAP Kinases in 15d-PGJ2-Induced Apoptosis in the Human Pancreatic Cancer Cell Line MIA PaCa-2,” Pancreas, vol. 28, no. 2, pp. 153–159, 2004.
[83]
A. Galli, E. Ceni, D. W. Crabb et al., “Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARγ independent mechanisms,” Gut, vol. 53, no. 11, pp. 1688–1697, 2004.
[84]
W. Motomura, M. Nagamine, S. Tanno et al., “Inhibition of cell invasion and morphological change by troglitazone in human pancreatic cancer cells,” Journal of Gastroenterology, vol. 39, no. 5, pp. 461–468, 2004.
[85]
G. Vitale, S. Zappavigna, M. Marra et al., “The PPAR-γ agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-β treated pancreatic cancer cells,” Biotechnology Advances, vol. 30, no. 1, pp. 169–184, 2012.
[86]
H. Koga, K. Selvendiran, R. Sivakumar et al., “PPARγ potentiates anticancer effects of gemcitabine on human pancreatic cancer cells,” International Journal of Oncology, vol. 40, no. 3, pp. 679–685, 2012.
[87]
P. Shah and S. Mudaliar, “Pioglitazone: side effect and safety profile,” Expert Opinion on Drug Safety, vol. 9, no. 2, pp. 347–354, 2010.
[88]
C. V. Rizos, M. S. Elisaf, D. P. Mikhailidis, and E. N. Liberopoulos, “How safe is the use of thiazolidinediones in clinical practice?” Expert Opinion on Drug Safety, vol. 8, no. 1, pp. 15–32, 2009.
