Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2012, Article ID 367450, 13 pages
http://dx.doi.org/10.1155/2012/367450
Review Article

Peroxisome Proliferator-Activated Receptor Gamma and Regulations by the Ubiquitin-Proteasome System in Pancreatic Cancer

1Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, BH06, Bugnon 46, 1011 Lausanne, Switzerland
2Division of Internal Medicine and Chronobiology Unit, Department of Medical Sciences, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy

Received 8 June 2012; Accepted 13 August 2012

Academic Editor: Valerio Pazienza

Copyright © 2012 Athina Stravodimou 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.

Linked References

  1. H. Manuel, “Pancreatic cancer,” The New England Journal of Medicine, vol. 362, no. 17, pp. 1605–1617, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. H. A. Burris III, M. J. Moore, J. Andersen et al., “Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial,” Journal of Clinical Oncology, vol. 15, no. 6, pp. 2403–2413, 1997. View at Google Scholar · View at Scopus
  3. T. Conroy, F. Desseigne, M. Ychou et al., “FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer,” The New England Journal of Medicine, vol. 364, no. 19, pp. 1817–1825, 2011. View at Publisher · View at Google Scholar · View at Scopus
  4. I. A. Voutsadakis, “Molecular predictors of gemcitabine response in pancreatic cancer,” World Journal of Gastrointestinal Oncology, vol. 3, no. 11, pp. 153–164, 2011. View at Google Scholar
  5. 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. View at Publisher · View at Google Scholar · View at Scopus
  6. C. Vigouroux, L. Fajas, E. Khallouf et al., “Human peroxisome proliferator-activated receptor-γ2: genetic mapping, identification of a variant in the coding sequence, and exclusion as the gene responsible for lipoatrophic diabetes,” Diabetes, vol. 47, no. 3, pp. 490–492, 1998. View at Publisher · View at Google Scholar · View at Scopus
  7. L. Fajas, D. Auboeuf, E. Raspé et al., “The organization, promoter analysis, and expression of the human PPARγ gene,” Journal of Biological Chemistry, vol. 272, no. 30, pp. 18779–18789, 1997. View at Publisher · View at Google Scholar · View at Scopus
  8. C. Huin, L. Corriveau, A. Bianchi et al., “Differential expression of peroxisome proliferator-activated receptors (PPARs) in the developing human fetal digestive tract,” Journal of Histochemistry and Cytochemistry, vol. 48, no. 5, pp. 603–611, 2000. View at Google Scholar · View at Scopus
  9. B. D. Abbott, C. R. Wood, A. M. Watkins, K. P. Das, and C. S. Lau, “Peroxisome proliferator-activated receptors alpha, beta, and gamma mRNA and protein expression in human fetal tissues,” PPAR Research, vol. 2010, Article ID 690907, 19 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. 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. View at Publisher · View at Google Scholar · View at Scopus
  11. S. Mandrup and A. Bugge, “Molecular mechanisms and genome-wide aspects of PPAR subtype specific transactivation,” PPAR Research, vol. 2010, Article ID 169506, 12 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. H. Yki-Järvinen, “Thiazolidinediones,” The New England Journal of Medicine, vol. 351, no. 11, pp. 1106–1118, 2004. View at Publisher · View at Google Scholar · View at Scopus
  13. C. Diradourian, J. Girard, and J. P. Pégorier, “Phosphorylation of PPARs: from molecular characterization to physiological relevance,” Biochimie, vol. 87, no. 1, pp. 33–38, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. H. S. Camp and S. R. Tafuri, “Regulation of peroxisome proliferator-activated receptor γ activity by mitogen-activated protein kinase,” Journal of Biological Chemistry, vol. 272, no. 16, pp. 10811–10816, 1997. View at Publisher · View at Google Scholar · View at Scopus
  15. D. Shao, S. M. Rangwala, S. T. Bailey, S. L. Krakow, M. J. Reginato, and M. A. Lazar, “Interdomain communication regulating ligand binding by PPAR-γ,” Nature, vol. 396, no. 6709, pp. 377–380, 1998. View at Publisher · View at Google Scholar · View at Scopus
  16. I. A. Voutsadakis, “Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer,” Atlas of Genetics and Cytogenetics in Oncology and Haematology, vol. 14, no. 11, pp. 1088–1099, 2010. View at Google Scholar
  17. B. A. Schulman and J. W. Harper, “Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways,” Nature Reviews Molecular Cell Biology, vol. 10, no. 5, pp. 319–331, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. S. J. L. van Wijk and H. T. M. Timmers, “The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins,” The FASEB Journal, vol. 24, no. 4, pp. 981–993, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. M. B. Metzger, V. A. Hristova, and A. M. Weissman, “HECT and RING finger families of E3 ubiquitin ligases at a glance,” Journal of Cell Science, vol. 125, pp. 531–537, 2012. View at Google Scholar
  20. W. Li and Y. Ye, “Polyubiquitin chains: functions, structures, and mechanisms,” Cellular and Molecular Life Sciences, vol. 65, no. 15, pp. 2397–2406, 2008. View at Publisher · View at Google Scholar · View at Scopus
  21. M. J. Clague, J. M. Coulson, and S. Urbé, “Cellular functions of the DUBs,” Journal of Cell Science, vol. 125, pp. 277–286, 2012. View at Google Scholar
  22. H. Walczak, K. Iwai, and I. Dikic, “Generation and physiological roles of linear ubiquitin chains,” BMC Biology, vol. 10, article 23, 6 pages, 2012. View at Publisher · View at Google Scholar
  23. C. Behrends and J. W. Harper, “Constructing and decoding unconventional ubiquitin chains,” Nature Structural and Molecular Biology, vol. 18, no. 5, pp. 520–528, 2011. View at Publisher · View at Google Scholar · View at Scopus
  24. I. A. Voutsadakis, “Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2: cancer,” Journal of Cellular and Molecular Medicine, vol. 11, no. 2, pp. 252–285, 2007. View at Publisher · View at Google Scholar · View at Scopus
  25. Y. Kravtsova-Ivantsiv and A. Ciechanover, “Non-canonical ubiquitin-based signals for proteasomal degradation,” Journal of Cell Science, vol. 125, pp. 539–548, 2012. View at Google Scholar
  26. K. Haglund and I. Dikic, “The role of ubiquitylation in receptor endocytosis and endosomal sorting,” Journal of Cell Science, vol. 125, pp. 265–275, 2012. View at Google Scholar
  27. S. Bergink and S. Jentsch, “Principles of ubiquitin and SUMO modifications in DNA repair,” Nature, vol. 458, no. 7237, pp. 461–467, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. A. Mocciaro and M. Rape, “Emerging regulatory mechanisms in ubiquitin-dependent cell cycle control,” Journal of Cell Science, vol. 125, pp. 255–263, 2012. View at Google Scholar
  29. H. D. Ulrich, “Ubiquitin and SUMO in DNA repair at a glance,” Journal of Cell Science, vol. 125, pp. 249–254, 2012. View at Google Scholar
  30. J. M. Winget and T. Mayor, “The diversity of ubiquitin recognition: hot spots and varied specificity,” Molecular Cell, vol. 38, no. 5, pp. 627–635, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Rechsteiner, “The 26S proteasome,” in Protein Degradation, R. J. Mayer, A. Ciechanover, and M. Rechsteiner, Eds., vol. 1, pp. 220–247, Wiley-VCH, New York, NY, USA, 2005. View at Google Scholar
  32. D. H. Wolf and W. Hilt, “The proteasome: a proteolytic nanomachine of cell regulation and waste disposal,” Biochimica et Biophysica Acta, vol. 1695, no. 1–3, pp. 19–31, 2004. View at Publisher · View at Google Scholar · View at Scopus
  33. J. L. Harris, P. B. Alper, J. Li, M. Rechsteiner, and B. J. Backes, “Substrate specificity of the human proteasome,” Chemistry and Biology, vol. 8, no. 12, pp. 1131–1141, 2001. View at Publisher · View at Google Scholar · View at Scopus
  34. Z. Nawaz and B. W. O'Malley, “Urban renewal in the nucleus: is protein turnover by proteasomes absolutely required for nuclear receptor-regulated transcription?” Molecular Endocrinology, vol. 18, no. 3, pp. 493–499, 2004. View at Publisher · View at Google Scholar · View at Scopus
  35. I. A. Voutsadakis and C. N. Papandreou, “The ubiquitin-proteasome system in prostate cancer and its transition to castration resistance,” Urologic Oncology. In press.
  36. V. Perissi, A. Aggarwal, C. K. Glass, D. W. Rose, and M. G. Rosenfeld, “A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors,” Cell, vol. 116, no. 4, pp. 511–526, 2004. View at Publisher · View at Google Scholar · View at Scopus
  37. S. Hauser, G. Adelmant, P. Sarraf, H. M. Wright, E. Mueller, and B. M. Spiegelman, “Degradation of the peroxisome proliferator-activated receptor γ is linked to ligand-dependent activation,” Journal of Biological Chemistry, vol. 275, no. 24, pp. 18527–18533, 2000. View at Publisher · View at Google Scholar · View at Scopus
  38. B. Lefebvre, Y. Benomar, A. Guédin et al., “Proteasomal degradation of retinoid X receptor α reprograms transcriptional activity of PPARγ in obese mice and humans,” Journal of Clinical Investigation, vol. 120, no. 5, pp. 1454–1468, 2010. View at Publisher · View at Google Scholar · View at Scopus
  39. P. Wei, D. Pan, C. Mao, and Y.-X. Wang, “RNF34 is a cold-regulated E3 ubiquitin ligase for PGC-1α and Modulates brown fat cell metabolism,” Molecular and Cellular Biology, vol. 32, no. 2, pp. 266–275, 2012. View at Publisher · View at Google Scholar · View at Scopus
  40. L. Amazit, A. Roseau, J. A. Khan et al., “Ligand-dependent degradation of SRC-1 is pivotal for progesterone receptor transcriptional activity,” Molecular Endocrinology, vol. 25, no. 3, pp. 394–408, 2011. View at Publisher · View at Google Scholar · View at Scopus
  41. C. Ferry, S. Gaouar, B. Fischer et al., “Cullin 3 mediates SRC-3 ubiquitination and degradation to control the retinoic acid response,” Journal of Biological Chemistry, vol. 108, no. 51, pp. 20603–20608, 2011. View at Google Scholar
  42. R. C. Wu, Q. Feng, D. M. Lonard, and B. W. O'Malley, “SRC-3 coactivator functional lifetime is regulated by a phosphor-dependent ubiquitin time clock,” Cell, vol. 129, no. 6, pp. 1125–1140, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. G. J. K. Praefcke, K. Hofmann, and R. J. Dohmen, “SUMO playing tag with ubiquitin,” Trends in Biochemical Sciences, vol. 37, no. 1, pp. 23–31, 2012. View at Google Scholar
  44. G. Pascual, A. L. Fong, S. Ogawa et al., “A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ,” Nature, vol. 437, no. 7059, pp. 759–763, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. S. S. Chung, B. Y. Ahn, M. Kim et al., “Control of adipogenesis by the SUMO-specific protease SENP2,” Molecular and Cellular Biology, vol. 30, no. 9, pp. 2135–2146, 2010. View at Publisher · View at Google Scholar · View at Scopus
  46. M. M. Rytinki and J. J. Palvimo, “SUMOylation attenuates the function of PGC-1α,” Journal of Biological Chemistry, vol. 284, no. 38, pp. 26184–26193, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Anbalagan, B. Huderson, L. Murphy, and B. G. Rowan, “Post-translational modifications of nuclear receptors and human disease,” Nuclear Receptor Signaling, vol. 10, pp. 1–13, 2012. View at Google Scholar
  48. M. Luconi, G. Cantini, and M. Serio, “Peroxisome proliferator-activated receptor gamma (PPARγ): is the genomic activity the only answer?” Steroids, vol. 75, no. 8-9, pp. 585–594, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. M. Toyota, Y. Miyazaki, S. Kitamura et al., “Peroxisome proliferator-activated receptor γ reduces the growth rate of pancreatic cancer cells through the reduction of cyclin D1,” Life Sciences, vol. 70, no. 13, pp. 1565–1575, 2002. View at Publisher · View at Google Scholar · View at Scopus
  50. S. Kawa, T. Nikaido, H. Unno, N. Usuda, K. Nakayama, and K. Kiyosawa, “Growth inhibition and differentiation of pancreatic cancer cell lines by PPARγ ligand troglitazone,” Pancreas, vol. 24, no. 1, pp. 1–7, 2002. View at Publisher · View at Google Scholar · View at Scopus
  51. 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. View at Publisher · View at Google Scholar · View at Scopus
  52. 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. View at Publisher · View at Google Scholar · View at Scopus
  53. H. Sawai, J. Liu, H. A. Reber, O. J. Hines, and G. Eibl, “Activation of peroxisome proliferator-activated receptor-γ decreases pancreatic cancer cell invasion through modulation of the plasminogen activator system,” Molecular Cancer Research, vol. 4, no. 3, pp. 159–167, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. 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. View at Publisher · View at Google Scholar · View at Scopus
  55. E. Ceni, T. Mello, M. Tarocchi et al., “Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells,” World Journal of Gastroenterology, vol. 11, no. 8, pp. 1122–1130, 2005. View at Google Scholar · View at Scopus
  56. 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 γ/retinoid X receptor α pathway,” Experimental Cell Research, vol. 289, no. 1, pp. 143–151, 2003. View at Publisher · View at Google Scholar · View at Scopus
  57. Y. Takeuchi, M. Takahashi, K. Sakano et al., “Suppression of N-nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamsters by pioglitazone, a ligand of peroxisome proliferator-activated receptor γ,” Carcinogenesis, vol. 28, no. 8, pp. 1692–1696, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. Y. W. 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. View at Publisher · View at Google Scholar · View at Scopus
  59. A. Nakajima, A. Tomimoto, K. Fujita et al., “Inhibition of peroxisome proliferator-activated receptor γ activity suppresses pancreatic cancer cell motility,” Cancer Science, vol. 99, no. 10, pp. 1892–1900, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. M. A. Abramson, A. Jazag, J. A. van der Zee, and E. E. Whang, “The molecular biology of pancreatic cancer,” Gastrointestinal Cancer Research, vol. 1, supplement 2, pp. S7–S12, 2007. View at Google Scholar
  61. A. D. Cox and C. J. Der, “Ras history: the saga continues,” Small GTPases, vol. 1, no. 1, pp. 2–27, 2010. View at Publisher · View at Google Scholar · View at Scopus
  62. B. Farrow and B. M. Evers, “Activation of PPARγ increases PTEN expression in pancreatic cancer cells,” Biochemical and Biophysical Research Communications, vol. 301, no. 1, pp. 50–53, 2003. View at Publisher · View at Google Scholar · View at Scopus
  63. 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. View at Publisher · View at Google Scholar · View at Scopus
  64. N. R. Leslie and M. Foti, “Non-genomic loss of PTEN function in cancer: not in my genes,” Trends in Pharmacological Sciences, vol. 32, no. 3, pp. 131–140, 2011. View at Publisher · View at Google Scholar · View at Scopus
  65. A. C. Schmukle and H. Walczak, “No one can whistle a symphony alone- how different ubiquitin linkages cooperate to orchestrate NF-κB activity,” Journal of Cell Science, vol. 125, pp. 549–559, 2012. View at Google Scholar
  66. S. Manenti, C. Delmas, and J. M. Darbon, “Cell adhesion protects c-Raf-1 against ubiquitin-dependent degradation by the proteasome,” Biochemical and Biophysical Research Communications, vol. 294, no. 5, pp. 976–980, 2002. View at Publisher · View at Google Scholar · View at Scopus
  67. Z. Lu, S. Xu, C. Joazeiro, M. H. Cobb, and T. Hunter, “The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2,” Molecular Cell, vol. 9, no. 5, pp. 945–956, 2002. View at Publisher · View at Google Scholar · View at Scopus
  68. P. Coulombe, G. Rodier, S. Pelletier, J. Pellerin, and S. Meloche, “Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation,” Molecular and Cellular Biology, vol. 23, no. 13, pp. 4542–4558, 2003. View at Publisher · View at Google Scholar · View at Scopus
  69. H. Guenou, K. Kaabeche, C. Dufour, H. Miraoui, and P. J. Marie, “Down-regulation of ubiquitin ligase Cbl induced by twist haploinsufficiency in Saethre-Chotzen syndrome results in increased PI3K/Akt signaling and osteoblast proliferation,” American Journal of Pathology, vol. 169, no. 4, pp. 1303–1311, 2006. View at Publisher · View at Google Scholar · View at Scopus
  70. M. Adachi, K. R. Katsumura, K. Fujii, S. Kobayashi, H. Aoki, and M. Matsuzaki, “Proteasome-dependent decrease in Akt by growth factors in vascular smooth muscle cells,” FEBS Letters, vol. 554, no. 1-2, pp. 77–80, 2003. View at Publisher · View at Google Scholar · View at Scopus
  71. J. Li, M. J. Poi, and M. D. Tsai, “Regulatory mechanisms of tumor suppressor P16INK4A and their relevance to cancer,” Biochemistry, vol. 50, no. 25, pp. 5566–5582, 2011. View at Publisher · View at Google Scholar · View at Scopus
  72. Z. Wang, S. Banerjee, A. Ahmad et al., “Activated K-ras and INK4a/Arf deficiency cooperate during the development of pancreatic cancer by activation of notch and NF-κB signaling pathways,” PLoS ONE, vol. 6, no. 6, Article ID e20537, 2011. View at Publisher · View at Google Scholar · View at Scopus
  73. O. Barbash, E. Egan, L. L. Pontano, J. Kosak, and J. A. Diehl, “Lysine 269 is essential for cyclin D1 ubiquitylation by the SCF Fbx4/αB-crystallin ligase and subsequent proteasome-dependent degradation,” Oncogene, vol. 28, no. 49, pp. 4317–4325, 2009. View at Publisher · View at Google Scholar · View at Scopus
  74. 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. View at Publisher · View at Google Scholar · View at Scopus
  75. H. Zand, A. Rhimipour, M. Bakhshayesh, M. Shafiee, I. Nour Mohammadi, and S. Salimi, “Involvement of PPAR-γ and p53 in DHA-induced apoptosis in Reh cells,” Molecular and Cellular Biochemistry, vol. 304, no. 1-2, pp. 71–77, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. C. Han, A. J. Demetris, G. K. Michalopoulos, Q. Zhan, J. H. Shelhamer, and T. Wu, “PPARγ ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21WAF1/Cip1 pathway,” Hepatology, vol. 38, no. 1, pp. 167–177, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. D. Bonofiglio, E. Cione, D. Vizza et al., “Bid as a potential target of apoptotic effects exerted by low doses of PPARγ and RXR ligands in breast cancer cells,” Cell Cycle, vol. 10, no. 14, pp. 2344–2354, 2011. View at Publisher · View at Google Scholar · View at Scopus
  78. H. Solomon, S. Madar, and V. Rotter, “Mutant p53 gain of function is interwoven into the hallmarks of cancer,” Journal of Pathology, vol. 225, no. 4, pp. 475–478, 2011. View at Google Scholar
  79. A. Blackford, O. K. Serrano, C. L. Wolfgang et al., “SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer,” Clinical Cancer Research, vol. 15, no. 14, pp. 4674–4679, 2009. View at Publisher · View at Google Scholar · View at Scopus
  80. J. Massagué, “TGFβ in cancer,” Cell, vol. 134, no. 2, pp. 215–230, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. K. Gong, Y.-F. Chen, P. Li et al., “Transforming growth factor-β inhibits myocardial PPARβ expression in pressure overload-induced cardiac fibrosis and remodeling in mice,” Journal of Hypertension, vol. 29, no. 9, pp. 1810–1819, 2011. View at Google Scholar
  82. V. Subramanian, J. Golledge, E. B. Heywood, D. Bruemmer, and A. Daugherty, “Regulation of peroxisome proliferator-activated receptor-γ by angiotensin II via transforming growth factor-β1-activated p38 mitogen-activated protein kinase in aortic smooth muscle cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 2, pp. 397–405, 2012. View at Google Scholar
  83. A. A. Kulkarni, T. H. Thatcher, K. C. Olsen, S. B. Maggirwar, R. P. Phipps, and P. J. Sime, “PPAR-γ ligands repress TGFβ-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis,” PLoS ONE, vol. 6, no. 1, Article ID e15909, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. J. H. Yu, K. H. Kim, and H. Kim, “SOCS3 and PPAR-γ ligands inhibit the expression of IL-6 and TGF-β1 by regulating JAK2/STAT3 signaling in pancreas,” International Journal of Biochemistry and Cell Biology, vol. 40, no. 4, pp. 677–688, 2008. View at Publisher · View at Google Scholar · View at Scopus
  85. Y. Inoue and T. Imamura, “Regulation of TGF-β family signaling by E3 ubiquitin ligases,” Cancer Science, vol. 99, no. 11, pp. 2107–2112, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. F. Huang and Y.-G. Chen, “Regulation of TGF-β receptor activity,” Cell and Bioscience, vol. 2, no. 9, pp. 1–10, 2012. View at Google Scholar
  87. S. Polo, “Signaling-mediated control of ubiquitin ligases in endocytosis,” BMC Biology, vol. 10, article 25, 9 pages, 2012. View at Publisher · View at Google Scholar
  88. L.-Y. Tang and Y. E. Zhang, “Non-degradative ubiquitination in Smad-dependent TGF-β signaling,” Cell and Bioscience, vol. 1, no. 43, pp. 1–5, 2011. View at Google Scholar
  89. A. Morén, U. Hellman, Y. Inada, T. Imamura, C. H. Heldin, and A. Moustakas, “Differential ubiquitination defines the functional status of the tumor suppressor Smad4,” Journal of Biological Chemistry, vol. 278, no. 35, pp. 33571–33582, 2003. View at Publisher · View at Google Scholar · View at Scopus
  90. B. Bao, Z. Wang, Y. Li et al., “The complexities of obesity and diabetes with the development and progression of pancreatic cancer,” Biochimica et Biophysica Acta, vol. 1815, no. 2, pp. 135–146, 2011. View at Publisher · View at Google Scholar · View at Scopus
  91. Y. Ben-Neriah and M. Karin, “Inflammation meets cancer, with NF-κB as the matchmaker,” Nature Immunology, vol. 12, no. 8, pp. 715–723, 2011. View at Google Scholar
  92. E. Maniati, M. Bossard, N. Cook et al., “Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice,” Journal of Clinical Investigation, vol. 121, no. 12, pp. 4685–4699, 2011. View at Google Scholar
  93. I. A. Voutsadakis, “Peroxisome Proliferator Activated Receptor-γ (PPARγ): roles in chronic inflammation and intestinal oncogenic transformation,” in From Inflammation to Cancer. Advances in Diagnosis and Therapy for Gastrointestinal and Hepatological Diseases, C. H. Cho and J. Yu, Eds., World Scientific, River Edge, NJ, USA, 2012. View at Google Scholar
  94. T. Asano, Y. Yao, J. Zhu, D. Li, J. L. Abbruzzese, and S. A. G. Reddy, “The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells,” Oncogene, vol. 23, no. 53, pp. 8571–8580, 2004. View at Publisher · View at Google Scholar · View at Scopus
  95. H. Ying, K. G. Elpek, A. Vinjamoori et al., “PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network,” Cancer Discovery, vol. 1, no. 2, pp. 158–169, 2011. View at Google Scholar
  96. M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998. View at Publisher · View at Google Scholar · View at Scopus
  97. C. Jiang, A. T. Ting, and B. Seed, “PPAR-γ agonists inhibit production of monocyte inflammatory cytokines,” Nature, vol. 391, no. 6662, pp. 82–86, 1998. View at Publisher · View at Google Scholar · View at Scopus
  98. M. A. Shields, S. Dangi-Garimella, A. J. Redig, and H. G. Munshi, “Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression,” Biochemical Journal, vol. 441, no. 2, pp. 541–552, 2012. View at Google Scholar
  99. D. A. Chapnick, L. Warner, J. Bernet, T. Rao, and X. Liu, “Partners in crime: the TGFβ and MAPK pathways in cancer progression,” Cell and Bioscience, vol. 1, no. 42, pp. 1–8, 2011. View at Google Scholar
  100. S. J. Lee, E. K. Yang, and S. G. Kim, “Peroxisome proliferator-activated receptor-γ and retinoic acid X receptor α represses the TGFβ1 gene via PTEN-mediated p70 ribosomal S6 kinase-1 inhibition: role for Zf9 dephosphorylation,” Molecular Pharmacology, vol. 70, no. 1, pp. 415–425, 2006. View at Google Scholar
  101. E. Burgermeister, D. Chuderland, T. Hanoch, M. Meyer, M. Liscovitch, and R. Seger, “Interaction with MEK causes nuclear export and downregulation of peroxisome proliferator-activated receptor γ,” Molecular and Cellular Biology, vol. 27, no. 3, pp. 803–817, 2007. View at Publisher · View at Google Scholar · View at Scopus
  102. R. Jaster, “Molecular regulation of pancreatic stellate cell function,” Molecular Cancer, vol. 3, article 26, 8 pages, 2004. View at Publisher · View at Google Scholar · View at Scopus
  103. M. V. Apte and J. S. Wilson, “Dangerous liaisons: pancreatic stellate cells and pancreatic cancer cells,” Journal of Gastroenterology and Hepatology, vol. 27, supplement 2, pp. 69–74, 2012. View at Google Scholar
  104. M. G. Bachem, M. Schünemann, M. Ramadani et al., “Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells,” Gastroenterology, vol. 128, no. 4, pp. 907–921, 2005. View at Publisher · View at Google Scholar · View at Scopus
  105. M. L. Kruse, S. Hopf-Jensen, C. Timke et al., “Differentiation potential of pancreatic fibroblastoid cells/stellate cells: effects of peroxisome proliferator-activated receptor gamma ligands,” International Journal of Cell Biology, vol. 2011, Article ID 816791, 11 pages, 2011. View at Google Scholar
  106. R. Kalluri and R. A. Weinberg, “The basics of epithelial-mesenchymal transition,” Journal of Clinical Investigation, vol. 119, no. 6, pp. 1420–1428, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. J. M. López-Nouoa and M. A. Nieto, “Inflammation and EMT: an alliance towards organ fibrosis and cancer progression,” EMBO Molecular Medicine, vol. 1, no. 6-7, pp. 303–314, 2009. View at Publisher · View at Google Scholar · View at Scopus
  108. S. A. Mani, W. Guo, M. J. Liao et al., “The epithelial-mesenchymal transition generates cells with properties of stem cells,” Cell, vol. 133, no. 4, pp. 704–715, 2008. View at Publisher · View at Google Scholar · View at Scopus
  109. S. Hamada, A. Masamune, T. Takikawa et al., “Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells,” Biochemical and Biophysical Research Communications, vol. 421, no. 2, pp. 349–354, 2012. View at Google Scholar
  110. K. Kikuta, A. Masamune, T. Watanabe et al., “Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells,” Biochemical and Biophysical Research Communications, vol. 403, no. 3-4, pp. 380–384, 2010. View at Publisher · View at Google Scholar · View at Scopus
  111. I. A. Voutsadakis, “Ubiquitination and the ubiquitin-proteasome system as regulators of transcription and transcription factors in epithelial mesenchymal transition of cancer,” Tumour Biology, vol. 33, no. 4, pp. 897–910, 2012. View at Google Scholar
  112. I. A. Voutsadakis, “The ubiquitin-proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer,” Journal of Biomedical Science, vol. 19, no. 67, pp. 1–13, 2012. View at Google Scholar
  113. A. K. Reka, H. Kurapati, V. R. Narala et al., “Peroxisome proliferator-activated receptor-γ activation inhibits tumor metastasis by antagonizing smad3-mediated epithelial-mesenchymal transition,” Molecular Cancer Therapeutics, vol. 9, no. 12, pp. 3221–3232, 2010. View at Publisher · View at Google Scholar · View at Scopus
  114. L. Chen, B. M. Necela, W. Su et al., “Peroxisome proliferator-activated receptor γ 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. View at Publisher · View at Google Scholar · View at Scopus
  115. R. A. Gupta and R. N. DuBois, “Controversy: PPARγ a target for treatment of colorectal cancer,” American Journal of Physiology, vol. 283, no. 2, pp. G266–G269, 2002. View at Google Scholar · View at Scopus
  116. A. J. Scheen, “Hepatotoxicity with thiazolidinediones: is it a class effect?” Drug Safety, vol. 24, no. 12, pp. 873–888, 2001. View at Google Scholar · View at Scopus
  117. L. Azoulay, H. Yin, K. B. Filion et al., “The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study,” British Medical Journal, vol. 344, Article ID e3645, 2012. View at Publisher · View at Google Scholar
  118. 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. View at Google Scholar
  119. G. D. Girnun, E. Naseri, S. B. Vafai et al., “Synergy between PPARγ ligands and platinum-based drugs in cancer,” Cancer Cell, vol. 11, no. 5, pp. 395–406, 2007. View at Publisher · View at Google Scholar · View at Scopus
  120. A. Galli, T. Mello, E. Ceni, E. Surrenti, and C. Surrenti, “The potential of antidiabetic thiazolidinediones for anticancer therapy,” Expert Opinion on Investigational Drugs, vol. 15, no. 9, pp. 1039–1049, 2006. View at Publisher · View at Google Scholar · View at Scopus
  121. A. A. Chanan-Khan, I. Borrello, K. P. Lee, and D. E. Reece, “Development of target-specific treatments in multiple myeloma,” British Journal of Haematology, vol. 151, no. 1, pp. 3–15, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. N. Awasthi, M. A. Schwarz, and R. E. Schwarz, “Proteasome inhibition enhances antitumour effects of gemcitabine in experimental pancreatic cancer,” HPB, vol. 11, no. 7, pp. 600–605, 2009. View at Publisher · View at Google Scholar · View at Scopus
  123. S. R. Alberts, N. R. Foster, R. F. Morton et al., “PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study,” Annals of Oncology, vol. 16, no. 10, pp. 1654–1661, 2005. View at Publisher · View at Google Scholar · View at Scopus
  124. M. Wang, B. C. Medeiros, H. P. Erba, D. J. DeAngelo, F. J. Giles, and R. T. Swords, “Targeting protein neddylation: a novel therapeutic strategy for the treatment of cancer,” Expert Opinion on Therapeutic Targets, vol. 15, no. 3, pp. 253–264, 2011. View at Publisher · View at Google Scholar · View at Scopus
  125. M. P. Dickens, R. Fitzgerald, and P. M. Fischer, “Small-molecule inhibitors of MDM2 as new anticancer therapeutics,” Seminars in Cancer Biology, vol. 20, no. 1, pp. 10–18, 2010. View at Publisher · View at Google Scholar · View at Scopus