Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2008, Article ID 102737, 15 pages
http://dx.doi.org/10.1155/2008/102737
Review Article

The Role of PPARs in Cancer

1Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
2The Center for Advanced Medical Engineering and Informatics, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
3Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Received 1 April 2008; Accepted 20 May 2008

Academic Editor: Dipak Panigrahy

Copyright © 2008 Keisuke Tachibana 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. D. J. Mangelsdorf, C. Thummel, M. Beato et al., “The nuclear receptor superfamily: the second decade,” Cell, vol. 83, no. 6, pp. 835–839, 1995. View at Google Scholar
  2. M.-H. Hsu, C. N. A. Palmer, W. Song, K. J. Griffin, and E. F. Johnson, “A carboxyl-terminal extension of the zinc finger domain contributes to the specificity and polarity of peroxisome proliferator-activated receptor DNA binding,” Journal of Biological Chemistry, vol. 273, no. 43, pp. 27988–27997, 1998. View at Publisher · View at Google Scholar
  3. P. Gervois, S. Chopin-Delannoy, A. Fadel et al., “Fibrates increase human REV-ERBα expression in liver via a novel peroxisome proliferator-activated receptor response element,” Molecular Endocrinology, vol. 13, no. 3, pp. 400–409, 1999. View at Google Scholar
  4. S. A. Kliewer, K. Umesono, D. J. Noonan, R. A. Heyman, and R. M. Evans, “Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors,” Nature, vol. 358, no. 6389, pp. 771–774, 1992. View at Publisher · View at Google Scholar · View at PubMed
  5. K. Schoonjans, B. Staels, and J. Auwerx, “Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression,” Journal of Lipid Research, vol. 37, no. 5, pp. 907–925, 1996. View at Google Scholar
  6. B. Desvergne and W. Wahli, “Peroxisome proliferator-activated receptors: nuclear control of metabolism,” Endocrine Reviews, vol. 20, no. 5, pp. 649–688, 1999. View at Google Scholar
  7. 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. View at Publisher · View at Google Scholar
  8. S. Mandard, M. Müller, and S. Kersten, “Peroxisome proliferator-activated receptor α target genes,” Cellular and Molecular Life Sciences, vol. 61, no. 4, pp. 393–416, 2004. View at Publisher · View at Google Scholar · View at PubMed
  9. G. Krey, O. Braissant, F. L'Horset et al., “Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay,” Molecular Endocrinology, vol. 11, no. 6, pp. 779–791, 1997. View at Publisher · View at Google Scholar
  10. 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. View at Publisher · View at Google Scholar · View at PubMed
  11. B. M. Forman, J. Chen, and R. M. Evans, “Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4312–4317, 1997. View at Publisher · View at Google Scholar
  12. S. A. Kliewer, S. S. Sundseth, S. A. Jones et al., “Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4318–4323, 1997. View at Publisher · View at Google Scholar
  13. J.-C. Fruchart, “Peroxisome proliferator-activated receptor-α activation and high-density lipoprotein metabolism,” The American Journal of Cardiology, vol. 88, no. 12, supplement 1, pp. 24–29, 2001. View at Publisher · View at Google Scholar
  14. B. Staels, J. Dallongeville, J. Auwerx, K. Schoonjans, E. Leitersdorf, and J.-C. Fruchart, “Mechanism of action of fibrates on lipid and lipoprotein metabolism,” Circulation, vol. 98, no. 19, pp. 2088–2093, 1998. View at Google Scholar
  15. Y.-X. Wang, C.-H. Lee, S. Tiep et al., “Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity,” Cell, vol. 113, no. 2, pp. 159–170, 2003. View at Publisher · View at Google Scholar
  16. N. S. Tan, L. Michalik, N. Noy et al., “Critical roles of PPARβ/δ in keratinocyte response to inflammation,” Genes & Development, vol. 15, no. 24, pp. 3263–3277, 2001. View at Publisher · View at Google Scholar · View at PubMed
  17. U. Dressel, T. L. Allen, J. B. Pippal, P. R. Rohde, P. Lau, and G. E. O. Muscat, “The peroxisome proliferator-activated receptor β/δ agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells,” Molecular Endocrinology, vol. 17, no. 12, pp. 2477–2493, 2003. View at Publisher · View at Google Scholar · View at PubMed
  18. A. Chawla, C.-H. Lee, Y. Barak et al., “PPARδ is a very low-density lipoprotein sensor in macrophages,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 3, pp. 1268–1273, 2003. View at Publisher · View at Google Scholar · View at PubMed
  19. T. Tanaka, J. Yamamoto, S. Iwasaki et al., “Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 26, pp. 15924–15929, 2003. View at Publisher · View at Google Scholar · View at PubMed
  20. G. D. Barish, V. A. Narkar, and R. M. Evans, “PPARδ: a dagger in the heart of the metabolic syndrome,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 590–597, 2006. View at Publisher · View at Google Scholar · View at PubMed
  21. S. Takahashi, T. Tanaka, T. Kodama, and J. Sakai, “Peroxisome proliferator-activated receptor δ (PPARδ), a novel target site for drug discovery in metabolic syndrome,” Pharmacological Research, vol. 53, no. 6, pp. 501–507, 2006. View at Publisher · View at Google Scholar · View at PubMed
  22. P. Tontonoz, E. Hu, R. A. Graves, A. I. Budavari, and B. M. Spiegelman, “mPPARγ2: tissue-specific regulator of an adipocyte enhancer,” Genes & Development, vol. 8, no. 10, pp. 1224–1234, 1994. View at Google Scholar
  23. 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
  24. L. Fajas, J.-C. Fruchart, and J. Auwerx, “PPARγ3 mRNA: a distinct PPARγ mRNA subtype transcribed from an independent promoter,” FEBS Letters, vol. 438, no. 1-2, pp. 55–60, 1998. View at Publisher · View at Google Scholar
  25. P. Tontonoz, E. Hu, and B. M. Spiegelman, “Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor,” Cell, vol. 79, no. 7, pp. 1147–1156, 1994. View at Google Scholar
  26. M. Lehrke and M. A. Lazar, “The many faces of PPARγ,” Cell, vol. 123, no. 6, pp. 993–999, 2005. View at Publisher · View at Google Scholar · View at PubMed
  27. J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ),” Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995. View at Publisher · View at Google Scholar
  28. K. Schoonjans, J. Peinado-Onsurbe, A.-M. Lefebvre et al., “PPARα and PPARγ activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene,” The EMBO Journal, vol. 15, no. 19, pp. 5336–5348, 1996. View at Google Scholar
  29. B. Staels, N. Vu-Dac, V. A. Kosykh et al., “Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates,” Journal of Clinical Investigation, vol. 95, no. 2, pp. 705–712, 1995. View at Google Scholar
  30. K. Tachibana, Y. Kobayashi, T. Tanaka et al., “Gene expression profiling of potential peroxisome proliferator-activated receptor (PPAR) target genes in human hepatoblastoma cell lines inducibly expressing PPAR isoforms,” Nuclear Receptor, vol. 3, article 3, pp. 1–17, 2005. View at Publisher · View at Google Scholar · View at PubMed
  31. N. Vu-Dac, S. Chopin-Delannoy, P. Gervois et al., “The nuclear receptors peroxisome proliferator-activated receptor α and rev-erbα mediate the species-specific regulation of apolipoprotein A-I expression by fibrates,” Journal of Biological Chemistry, vol. 273, no. 40, pp. 25713–25720, 1998. View at Publisher · View at Google Scholar
  32. N. Vu-Dac, K. Schoonjans, V. Kosykh et al., “Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor,” Journal of Clinical Investigation, vol. 96, no. 2, pp. 741–750, 1995. View at Google Scholar
  33. S. A. Saha, L. G. Kizhakepunnur, A. Bahekar, and R. R. Arora, “The role of fibrates in the prevention of cardiovascular disease—a pooled meta-analysis of long-term randomized placebo-controlled clinical trials,” American Heart Journal, vol. 154, no. 5, pp. 943–953, 2007. View at Publisher · View at Google Scholar · View at PubMed
  34. J. Ashby, A. Brady, C. R. Elcombe et al., “Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis,” Human & Experimental Toxicology, vol. 13, pp. S1–S117, 1994. View at Google Scholar
  35. R. Hess, W. Stäubli, and W. Riess, “Nature of the hepatomegalic effect produced by ethyl-chlorophenoxy-isobutyrate in the rat,” Nature, vol. 208, no. 5013, pp. 856–858, 1965. View at Publisher · View at Google Scholar
  36. J. K. Reddy, D. L. Azarnoff, and C. E. Hignite, “Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens,” Nature, vol. 283, no. 5745, pp. 397–398, 1980. View at Google Scholar
  37. J. M. Peters, R. C. Cattley, and F. J. Gonzalez, “Role of PPARα in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643,” Carcinogenesis, vol. 18, no. 11, pp. 2029–2033, 1997. View at Publisher · View at Google Scholar
  38. S. K. Goel, N. D. Lalwani, and J. K. Reddy, “Peroxisome proliferation and lipid peroxidation in rat liver,” Cancer Research, vol. 46, no. 3, pp. 1324–1330, 1986. View at Google Scholar
  39. H. Ozasa, S. Miyazawa, S. Furuta, T. Osumi, and T. Hashimoto, “Induction of peroxisomal β-oxidation enzymes in primary cultured rat hepatocytes by clofibric acid,” Journal of Biochemistry, vol. 97, no. 5, pp. 1273–1278, 1985. View at Google Scholar
  40. J. K. Reddy, S. K. Goel, M. R. Nemali et al., “Transcriptional regulation of peroxisomal fatty acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase in rat liver by peroxisome proliferators,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 6, pp. 1747–1751, 1986. View at Google Scholar
  41. S. Furuta, S. Miyazawa, and T. Hashimoto, “Biosynthesis of enzymes of peroxisomal β-oxidation,” Journal of Biochemistry, vol. 92, no. 2, pp. 319–326, 1982. View at Google Scholar
  42. T. Osumi, J.-K. Wen, and T. Hashimoto, “Two cis-acting regulatory sequences in the peroxisome proliferator-responsive enhancer region of rat acyl-CoA oxidase gene,” Biochemical and Biophysical Research Communications, vol. 175, no. 3, pp. 866–871, 1991. View at Publisher · View at Google Scholar
  43. J. D. Tugwood, I. Issemann, R. G. Anderson, K. R. Bundell, W. L. McPheat, and S. Green, “The mouse peroxisome proliferator activated receptor recognizes a response element in the 5 flanking sequence of the rat acyl CoA oxidase gene,” The EMBO Journal, vol. 11, no. 2, pp. 433–439, 1992. View at Google Scholar
  44. S. Chu, Q. Huang, K. Alvares, A. V. Yeldandi, M. S. Rao, and J. K. Reddy, “Transformation of mammalian cells by overexpressing H2O2-generating peroxisomal fatty acyl-CoA oxidase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 15, pp. 7080–7084, 1995. View at Publisher · View at Google Scholar
  45. A. V. Yeldandi, M. S. Rao, and J. K. Reddy, “Hydrogen peroxide generation in peroxisome proliferator-induced oncogenesis,” Mutation Research, vol. 448, no. 2, pp. 159–177, 2000. View at Publisher · View at Google Scholar
  46. E. S. Henle and S. Linn, “Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide,” Journal of Biological Chemistry, vol. 272, no. 31, pp. 19095–19098, 1997. View at Publisher · View at Google Scholar
  47. M. Sekiguchi and T. Tsuzuki, “Oxidative nucleotide damage: consequences and prevention,” Oncogene, vol. 21, no. 58, pp. 8895–8904, 2002. View at Publisher · View at Google Scholar · View at PubMed
  48. M. S. Rao, N. D. Lalwani, T. K. Watanabe, and J. K. Reddy, “Inhibitory effect of antioxidants ethoxyquin and 2(3)-tert-butyl-4-hydroxyanisole on hepatic tumorigenesis in rats fed ciprofibrate, a peroxisome proliferator,” Cancer Research, vol. 44, no. 3, pp. 1072–1076, 1984. View at Google Scholar
  49. J. K. Reddy, M. S. Rao, and D. E. Moody, “Hepatocellular carcinomas in acatalasemic mice treated with nafenopin, a hypolipidemic peroxisome proliferator,” Cancer Research, vol. 36, no. 4, pp. 1211–1217, 1976. View at Google Scholar
  50. F. Bieri, P. Bentley, F. Waechter, and W. Stäubli, “Use of primary cultures of adult rat hepatocytes to investigate mechanisms of action of nafenopin, a hepatocarcinogenic peroxisome proliferator,” Carcinogenesis, vol. 5, no. 8, pp. 1033–1039, 1984. View at Google Scholar
  51. J. M. Peters, T. Aoyama, R. C. Cattley, U. Nobumitsu, T. Hashimoto, and F. J. Gonzalez, “Role of peroxisome proliferator-activated receptor α in altered cell cycle regulation in mouse liver,” Carcinogenesis, vol. 19, no. 11, pp. 1989–1994, 1998. View at Google Scholar
  52. T. Hays, I. Rusyn, A. M. Burns et al., “Role of peroxisome proliferator-activated receptor-α (PPARα) in bezafibrate-induced hepatocarcinogenesis and cholestasis,” Carcinogenesis, vol. 26, no. 1, pp. 219–227, 2005. View at Publisher · View at Google Scholar · View at PubMed
  53. A. C. Bayly, R. A. Roberts, and C. Dive, “Suppression of liver cell apoptosis in vitro by the non-genotoxic hepatocarcinogen and peroxisome proliferator nafenopin,” Journal of Cell Biology, vol. 125, no. 1, pp. 197–203, 1994. View at Google Scholar
  54. A. C. Bayly, N. J. French, C. Dive, and R. A. Roberts, “Non-genotoxic hepatocarcinogenesis in vitro: the FaO hepatoma line responds to peroxisome proliferators and retains the ability to undergo apoptosis,” Journal of Cell Science, vol. 104, no. 2, pp. 307–315, 1993. View at Google Scholar
  55. C. N. A. Palmer, M.-H. Hsu, K. J. Griffin, J. L. Raucy, and E. F. Johnson, “Peroxisome proliferator activated receptor-α expression in human liver,” Molecular Pharmacology, vol. 53, no. 1, pp. 14–22, 1998. View at Google Scholar
  56. A. IJpenberg, N. S. Tan, L. Gelman et al., “In vivo activation of PPAR target genes by RXR homodimers,” The EMBO Journal, vol. 23, no. 10, pp. 2083–2091, 2004. View at Publisher · View at Google Scholar · View at PubMed
  57. R. Hertz, J. Bishara-Shieban, and J. Bar-Tana, “Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III,” Journal of Biological Chemistry, vol. 270, no. 22, pp. 13470–13475, 1995. View at Google Scholar
  58. T. Miyamoto, A. Kaneko, T. Kakizawa et al., “Inhibition of peroxisome proliferator signaling pathways by thyroid hormone receptor. Competitive binding to the response element,” Journal of Biological Chemistry, vol. 272, no. 12, pp. 7752–7758, 1997. View at Publisher · View at Google Scholar
  59. K. S. Miyata, B. Zhang, S. L. Marcus, J. P. Capone, and R. A. Rachubinski, “Chicken ovalbumin upstream promoter transcription factor (COUP-TF) binds to a peroxisome proliferator-responsive element and antagonizes peroxisome proliferator-mediated signaling,” Journal of Biological Chemistry, vol. 268, no. 26, pp. 19169–19172, 1993. View at Google Scholar
  60. K. Han, H. Song, I. Moon et al., “Utilization of DR1 as true RARE in regulating the Ssm, a novel retinoic acid-target gene in the mouse testis,” Journal of Endocrinology, vol. 192, no. 3, pp. 539–551, 2007. View at Publisher · View at Google Scholar · View at PubMed
  61. I. P. Torra, Y. Jamshidi, D. M. Flavell, J.-C. Fruchart, and B. Staels, “Characterization of the human PPARα promoter: identification of a functional nuclear receptor response element,” Molecular Endocrinology, vol. 16, no. 5, pp. 1013–1028, 2002. View at Publisher · View at Google Scholar
  62. H. Nakshatri and P. Bhat-Nakshatri, “Multiple parameters determine the specificity of transcriptional response by nuclear receptors HNF-4, ARP-1, PPAR, RAR and RXR through common response elements,” Nucleic Acids Research, vol. 26, no. 10, pp. 2491–2499, 1998. View at Publisher · View at Google Scholar
  63. M.-H. Hsu, Ü. Savas, K. J. Griffin, and E. F. Johnson, “Identification of peroxisome proliferator-responsive human genes by elevated expression of the peroxisome proliferator-activated receptor α in HepG2 cells,” Journal of Biological Chemistry, vol. 276, no. 30, pp. 27950–27958, 2001. View at Publisher · View at Google Scholar · View at PubMed
  64. J. W. Lawrence, Y. Li, S. Chen et al., “Differential gene regulation in human versus rodent hepatocytes by peroxisome proliferator-activated receptor (PPAR) α. PPARα fails to induce peroxisome proliferation-associated genes in human cells independently of the level of receptor expression,” Journal of Biological Chemistry, vol. 276, no. 34, pp. 31521–31527, 2001. View at Publisher · View at Google Scholar · View at PubMed
  65. R. A. Roberts, N. H. James, N. J. Woodyatt, N. Macdonald, and J. D. Tugwood, “Evidence for the suppression of apoptosis by the peroxisome proliferator activated receptor alpha (PPARα),” Carcinogenesis, vol. 19, no. 1, pp. 43–48, 1998. View at Publisher · View at Google Scholar
  66. P. Gervois, I. P. Torra, G. Chinetti et al., “A truncated human peroxisome proliferator-activated receptor α splice variant with dominant negative activity,” Molecular Endocrinology, vol. 13, no. 9, pp. 1535–1549, 1999. View at Google Scholar
  67. N. J. Woodyatt, K. G. Lambe, K. A. Myers, J. D. Tugwood, and R. A. Roberts, “The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population: significance for species differences in response to PPs,” Carcinogenesis, vol. 20, no. 3, pp. 369–372, 1999. View at Google Scholar
  68. K. G. Lambe, N. J. Woodyatt, N. Macdonald, S. Chevalier, and R. A. Roberts, “Species differences in sequence and activity of the peroxisome proliferator response element (PPRE) within the acyl CoA oxidase gene promoter,” Toxicology Letters, vol. 110, no. 1-2, pp. 119–127, 1999. View at Publisher · View at Google Scholar
  69. S. C. Hasmall, N. H. James, N. Macdonald, A. R. Soames, and R. A. Roberts, “Species differences in response to diethylhexylphthalate: suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression,” Archives of Toxicology, vol. 74, no. 2, pp. 85–91, 2000. View at Publisher · View at Google Scholar
  70. C. Cheung, T. E. Akiyama, J. M. Ward et al., “Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor α,” Cancer Research, vol. 64, no. 11, pp. 3849–3854, 2004. View at Publisher · View at Google Scholar · View at PubMed
  71. Q. Yang, T. Nagano, Y. Shah, C. Cheung, S. Ito, and F. J. Gonzalez, “The PPARα-humanized mouse: a model to investigate species differences in liver toxicity mediated by PPARα,” Toxicological Sciences, vol. 101, no. 1, pp. 132–139, 2008. View at Publisher · View at Google Scholar · View at PubMed
  72. F. J. Gonzalez and Y. M. Shah, “PPARα: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators,” Toxicology, vol. 246, no. 1, pp. 2–8, 2008. View at Publisher · View at Google Scholar · View at PubMed
  73. K. Morimura, C. Cheung, J. M. Ward, J. K. Reddy, and F. J. Gonzalez, “Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor α to Wy-14,643-induced liver tumorigenesis,” Carcinogenesis, vol. 27, no. 5, pp. 1074–1080, 2006. View at Publisher · View at Google Scholar · View at PubMed
  74. Y. M. Shah, K. Morimura, Q. Yang, T. Tanabe, M. Takagi, and F. J. Gonzalez, “Peroxisome proliferator-activated receptor α regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation,” Molecular and Cellular Biology, vol. 27, no. 12, pp. 4238–4247, 2007. View at Publisher · View at Google Scholar · View at PubMed
  75. G. Meister and T. Tuschl, “Mechanisms of gene silencing by double-stranded RNA,” Nature, vol. 431, no. 7006, pp. 343–349, 2004. View at Publisher · View at Google Scholar · View at PubMed
  76. B. Zhang, X. Pan, G. P. Cobb, and T. A. Anderson, “microRNAs as oncogenes and tumor suppressors,” Developmental Biology, vol. 302, no. 1, pp. 1–12, 2007. View at Publisher · View at Google Scholar · View at PubMed
  77. 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. View at Publisher · View at Google Scholar
  78. 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. View at Publisher · View at Google Scholar · View at PubMed
  79. J. Groden, A. Thliveris, W. Samowitz et al., “Identification and characterization of the familial adenomatous polyposis coli gene,” Cell, vol. 66, no. 3, pp. 589–600, 1991. View at Google Scholar
  80. K. W. Kinzler and B. Vogelstein, “Lessons from hereditary colorectal cancer,” Cell, vol. 87, no. 2, pp. 159–170, 1996. View at Publisher · View at Google Scholar
  81. S. M. Powell, N. Zilz, Y. Beazer-Barclay et al., “APC mutations occur early during colorectal tumorigenesis,” Nature, vol. 359, no. 6392, pp. 235–237, 1992. View at Publisher · View at Google Scholar · View at PubMed
  82. K. W. Kinzler, M. C. Nilbert, L.-K. Su et al., “Identification of FAP locus genes from chromosome 5q21,” Science, vol. 253, no. 5020, pp. 661–665, 1991. View at Google Scholar
  83. I. Nishisho, Y. Nakamura, Y. Miyoshi et al., “Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients,” Science, vol. 253, no. 5020, pp. 665–669, 1991. View at Google Scholar
  84. P. Polakis, “The many ways of Wnt in cancer,” Current Opinion in Genetics & Development, vol. 17, no. 1, pp. 45–51, 2007. View at Publisher · View at Google Scholar · View at PubMed
  85. O. Tetsu and F. McCormick, “β-catenin regulates expression of cyclin D1 in colon carcinoma cells,” Nature, vol. 398, no. 6726, pp. 422–426, 1999. View at Publisher · View at Google Scholar · View at PubMed
  86. T.-C. He, A. B. Sparks, C. Rago et al., “Identification of c-MYC as a target of the APC pathway,” Science, vol. 281, no. 5382, pp. 1509–1512, 1998. View at Publisher · View at Google Scholar
  87. E. R. Fearon and B. Vogelstein, “A genetic model for colorectal tumorigenesis,” Cell, vol. 61, no. 5, pp. 759–767, 1990. View at Publisher · View at Google Scholar
  88. J. S. Sebolt-Leopold and R. Herrera, “Targeting the mitogen-activated protein kinase cascade to treat cancer,” Nature Reviews Cancer, vol. 4, no. 12, pp. 937–947, 2004. View at Publisher · View at Google Scholar · View at PubMed
  89. 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. View at Google Scholar
  90. R. A. Gupta and R. N. DuBois, “Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2,” Nature Reviews Cancer, vol. 1, no. 1, pp. 11–21, 2001. View at Google Scholar
  91. D. L. DeWitt, “Cox-2-selective inhibitors: the new super aspirins,” Molecular Pharmacology, vol. 55, no. 4, pp. 625–631, 1999. View at Google Scholar
  92. K. Subbaramaiah and A. J. Dannenberg, “Cyclooxygenase 2: a molecular target for cancer prevention and treatment,” Trends in Pharmacological Sciences, vol. 24, no. 2, pp. 96–102, 2003. View at Publisher · View at Google Scholar
  93. W. L. Smith, D. L. DeWitt, and R. M. Garavito, “Cyclooxygenases: structural, cellular, and molecular biology,” Annual Review of Biochemistry, vol. 69, pp. 145–182, 2000. View at Publisher · View at Google Scholar · View at PubMed
  94. C. E. Eberhart, R. J. Coffey, A. Radhika, F. M. Giardiello, S. Ferrenbach, and R. N. DuBois, “Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas,” Gastroenterology, vol. 107, no. 4, pp. 1183–1188, 1994. View at Google Scholar
  95. M. Oshima, J. E. Dinchuk, S. L. Kargman et al., “Suppression of intestinal polyposis in ApcΔ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2),” Cell, vol. 87, no. 5, pp. 803–809, 1996. View at Publisher · View at Google Scholar
  96. S. Pugh and G. A. O. Thomas, “Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2,” Gut, vol. 35, no. 5, pp. 675–678, 1994. View at Google Scholar
  97. H. Sheng, J. Shao, M. K. Washington, and R. N. DuBois, “Prostaglandin E2 increases growth and motility of colorectal carcinoma cells,” Journal of Biological Chemistry, vol. 276, no. 21, pp. 18075–18081, 2001. View at Publisher · View at Google Scholar · View at PubMed
  98. D. Wang, H. Wang, Q. Shi et al., “Prostaglandin E2 promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor δ,” Cancer Cell, vol. 6, no. 3, pp. 285–295, 2004. View at Publisher · View at Google Scholar · View at PubMed
  99. L. Xu, C. Han, and T. Wu, “A novel positive feedback loop between peroxisome proliferator-activated receptor-δ and prostaglandin E2 signaling pathways for human cholangiocarcinoma cell growth,” Journal of Biological Chemistry, vol. 281, no. 45, pp. 33982–33996, 2006. View at Publisher · View at Google Scholar · View at PubMed
  100. 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. View at Publisher · View at Google Scholar · View at PubMed
  101. R. A. Gupta, D. Wang, S. Katkuri, H. Wang, S. K. Dey, and R. N. DuBois, “Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-δ accelerates intestinal adenoma growth,” Nature Medicine, vol. 10, no. 3, pp. 245–247, 2004. View at Publisher · View at Google Scholar · View at PubMed
  102. 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. View at Publisher · View at Google Scholar · View at PubMed
  103. L. Piqueras, A. R. Reynolds, K. M. Hodivala-Dilke et al., “Activation of PPARβ/δ induces endothelial cell proliferation and angiogenesis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 1, pp. 63–69, 2007. View at Publisher · View at Google Scholar · View at PubMed
  104. R. L. Stephen, M. C. U. Gustafsson, M. Jarvis et al., “Activation of peroxisome proliferator-activated receptor δ stimulates the proliferation of human breast and prostate cancer cell lines,” Cancer Research, vol. 64, no. 9, pp. 3162–3170, 2004. View at Publisher · View at Google Scholar
  105. I. Shureiqi, K. J. Wojno, J. A. Poore et al., “Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers,” Carcinogenesis, vol. 20, no. 10, pp. 1985–1995, 1999. View at Publisher · View at Google Scholar
  106. I. Shureiqi, W. Jiang, X. Zuo et al., “The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-δ to induce apoptosis in colorectal cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 17, pp. 9968–9973, 2003. View at Publisher · View at Google Scholar · View at PubMed
  107. I. Shureiqi, D. Chen, J. J. Lee et al., “15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells,” Journal of the National Cancer Institute, vol. 92, no. 14, pp. 1136–1142, 2000. View at Publisher · View at Google Scholar
  108. 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. View at Publisher · View at Google Scholar · View at PubMed
  109. H. E. Marin, M. A. Peraza, A. N. Billin et al., “Ligand activation of peroxisome proliferator-activated receptor β inhibits colon carcinogenesis,” Cancer Research, vol. 66, no. 8, pp. 4394–4401, 2006. View at Publisher · View at Google Scholar · View at PubMed
  110. N. Di-Poï, B. Desvergne, L. Michalik, and W. Wahli, “Transcriptional repression of peroxisome proliferator-activated receptor β/δ in murine keratinocytes by CCAAT/enhancer-binding proteins,” Journal of Biological Chemistry, vol. 280, no. 46, pp. 38700–38710, 2005. View at Publisher · View at Google Scholar · View at PubMed
  111. T. W. Dunlop, S. Väisänen, C. Frank, F. Molnár, L. Sinkkonen, and C. Carlberg, “The human peroxisome proliferator-activated receptor δ gene is a primary target of 1α,25-dihydroxyvitamin D3 and its nuclear receptor,” Journal of Molecular Biology, vol. 349, no. 2, pp. 248–260, 2005. View at Publisher · View at Google Scholar · View at PubMed
  112. H. E. Hollingshead, R. L. Killins, M. G. Borland et al., “Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands do not potentiate growth of human cancer cell lines,” Carcinogenesis, vol. 28, no. 12, pp. 2641–2649, 2007. View at Publisher · View at Google Scholar · View at PubMed
  113. Y. Barak, D. Liao, W. He et al., “Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 1, pp. 303–308, 2002. View at Publisher · View at Google Scholar · View at PubMed
  114. 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. View at Publisher · View at Google Scholar · View at PubMed
  115. D. J. Kim, M. T. Bility, A. N. Billin, T. M. Willson, F. J. Gonzalez, and J. M. Peters, “PPARβ/δ selectively induces differentiation and inhibits cell proliferation,” Cell Death & Differentiation, vol. 13, no. 1, pp. 53–60, 2006. View at Publisher · View at Google Scholar · View at PubMed
  116. M. Schmuth, C. M. Haqq, W. J. Cairns et al., “Peroxisome proliferator-activated receptor (PPAR)-β/δ stimulates differentiation and lipid accumulation in keratinocytes,” Journal of Investigative Dermatology, vol. 122, no. 4, pp. 971–983, 2004. View at Publisher · View at Google Scholar · View at PubMed
  117. T. Hatae, M. Wada, C. Yokoyama, M. Shimonishi, and T. Tanabe, “Prostacyclin-dependent apoptosis mediated by PPARδ,” Journal of Biological Chemistry, vol. 276, no. 49, pp. 46260–46267, 2001. View at Publisher · View at Google Scholar · View at PubMed
  118. N. Di-Poï, 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. View at Publisher · View at Google Scholar
  119. Y. Yin, R. G. Russell, L. E. Dettin et al., “Peroxisome proliferator-activated receptor δ and γ agonists differentially alter tumor differentiation and progression during mammary carcinogenesis,” Cancer Research, vol. 65, no. 9, pp. 3950–3957, 2005. View at Publisher · View at Google Scholar · View at PubMed
  120. A. D. Burdick, M. T. Bility, E. E. Girroir et al., “Ligand activation of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits cell growth of human N/TERT-1 keratinocytes,” Cellular Signalling, vol. 19, no. 6, pp. 1163–1171, 2007. View at Publisher · View at Google Scholar · View at PubMed
  121. E. E. Girroir, H. E. Hollingshead, A. N. Billin et al., “Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines,” Toxicology, vol. 243, no. 1-2, pp. 236–243, 2008. View at Publisher · View at Google Scholar · View at PubMed
  122. A.-M. Krogsdam, C. A. F. Nielsen, S. Neve et al., “Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor δ-mediated transactivation,” Biochemical Journal, vol. 363, no. 1, pp. 157–165, 2002. View at Publisher · View at Google Scholar
  123. Y. Shi, M. Hon, and R. M. Evans, “The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 5, pp. 2613–2618, 2002. View at Publisher · View at Google Scholar · View at PubMed
  124. C.-H. Lee, A. Chawla, N. Urbiztondo, D. Liao, W. A. Boisvert, and R. M. Evans, “Transcriptional repression of atherogenic inflammation: modulation by PPARδ,” Science, vol. 302, no. 5644, pp. 453–457, 2003. View at Publisher · View at Google Scholar · View at PubMed
  125. T. Fauti, S. Müller-Brüsselbach, M. Kreutzer et al., “Induction of PPARβ and prostacyclin (PGI2) synthesis by Raf signaling: failure of PGI2 to activate PPARβ,” FEBS Journal, vol. 273, no. 1, pp. 170–179, 2006. View at Publisher · View at Google Scholar · View at PubMed
  126. G. K. Schwartz and M. A. Shah, “Targeting the cell cycle: a new approach to cancer therapy,” Journal of Clinical Oncology, vol. 23, no. 36, pp. 9408–9421, 2005. View at Publisher · View at Google Scholar · View at PubMed
  127. E. Bremer, G. van Dam, B. J. Kroesen, L. de Leij, and W. Helfrich, “Targeted induction of apoptosis for cancer therapy: current progress and prospects,” Trends in Molecular Medicine, vol. 12, no. 8, pp. 382–393, 2006. View at Publisher · View at Google Scholar · View at PubMed
  128. C. Grommes, G. E. Landreth, and M. T. Heneka, “Antineoplastic effects of peroxisome proliferator-activated receptor γ agonists,” The Lancet Oncology, vol. 5, no. 7, pp. 419–429, 2004. View at Publisher · View at Google Scholar · View at PubMed
  129. S. Theocharis, A. Margeli, P. Vielh, and G. Kouraklis, “Peroxisome proliferator-activated receptor-γ ligands as cell-cycle modulators,” Cancer Treatment Reviews, vol. 30, no. 6, pp. 545–554, 2004. View at Publisher · View at Google Scholar · View at PubMed
  130. J. A. Brockman, R. A. Gupta, and R. N. DuBois, “Activation of PPARγ leads to inhibition of anchorage-independent growth of human colorectal cancer cells,” Gastroenterology, vol. 115, no. 5, pp. 1049–1055, 1998. View at Publisher · View at Google Scholar
  131. E. Osawa, A. Nakajima, K. Wada et al., “Peroxisome proliferator-activated receptor γ ligands suppress colon carcinogenesis induced by azoxymethane in mice,” Gastroenterology, vol. 124, no. 2, pp. 361–367, 2003. View at Publisher · View at Google Scholar · View at PubMed
  132. T. Shimada, K. Kojima, K. Yoshiura, H. Hiraishi, and A. Terano, “Characteristics of the peroxisome proliferator activated receptor γ (PPARγ) ligand induced apoptosis in colon cancer cells,” Gut, vol. 50, no. 5, pp. 658–664, 2002. View at Publisher · View at Google Scholar
  133. 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. View at Publisher · View at Google Scholar
  134. 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. View at Publisher · View at Google Scholar
  135. 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. View at Publisher · View at Google Scholar · View at PubMed
  136. 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. View at Publisher · View at Google Scholar · View at PubMed
  137. 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. View at Publisher · View at Google Scholar
  138. M. A. K. Rumi, H. Sato, S. Ishihara, C. Ortega, Y. Kadowaki, and Y. Kinoshita, “Growth inhibition of esophageal squamous carcinoma cells by peroxisome proliferator-activated receptor-γ ligands,” Journal of Laboratory and Clinical Medicine, vol. 140, no. 1, pp. 17–26, 2002. View at Publisher · View at Google Scholar
  139. 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. View at Publisher · View at Google Scholar · View at PubMed
  140. W. Motomura, T. Okumura, N. Takahashi, T. Obara, and Y. Kohgo, “Activation of peroxisome proliferator-activated receptor γ by troglitazone inhibits cell growth through the increase of p27Kip1 in human pancreatic carcinoma cells,” Cancer Research, vol. 60, no. 19, pp. 5558–5564, 2000. View at Google Scholar
  141. H. Koga, S. Sakisaka, M. Harada et al., “Involvement of p21WAF1/Cip1, p27Kip1, and p18INK4c in troglitazone-induced cell-cycle arrest in human hepatoma cell lines,” Hepatology, vol. 33, no. 5, pp. 1087–1097, 2001. View at Publisher · View at Google Scholar · View at PubMed
  142. P. Ferruzzi, E. Ceni, M. Tarocchi et al., “Thiazolidinediones inhibit growth and invasiveness of the human adrenocortical cancer cell line H295R,” Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 3, pp. 1332–1339, 2005. View at Publisher · View at Google Scholar · View at PubMed
  143. T.-H. Chang and E. Szabo, “Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor γ in non-small cell lung cancer,” Cancer Research, vol. 60, no. 4, pp. 1129–1138, 2000. View at Google Scholar
  144. E. Mueller, M. Smith, P. Sarraf et al., “Effects of ligand activation of peroxisome proliferator-activated receptor γ in human prostate cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 20, pp. 10990–10995, 2000. View at Publisher · View at Google Scholar · View at PubMed
  145. P. Tontonoz, S. Singer, B. M. Forman et al., “Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor γ and the retinoid X receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 1, pp. 237–241, 1997. View at Publisher · View at Google Scholar
  146. K. Ohta, T. Endo, K. Haraguchi, J. M. Hershman, and T. Onaya, “Ligands for peroxisome proliferator-activated receptor γ inhibit growth and induce apoptosis of human papillary thyroid carcinoma cells,” The Journal of Clinical Endocrinology & Metabolism, vol. 86, no. 5, pp. 2170–2177, 2001. View at Publisher · View at Google Scholar
  147. Y.-F. Guan, Y.-H. Zhang, R. M. Breyer, L. Davis, and M. D. Breyer, “Expression of peroxisome proliferator-activated receptor γ (PPARγ) in human transitional bladder cancer and its role in inducing cell death,” Neoplasia, vol. 1, no. 4, pp. 330–339, 1999. View at Publisher · View at Google Scholar
  148. K. Inoue, Y. Kawahito, Y. Tsubouchi et al., “Expression of peroxisome proliferator-activated receptor γ in renal cell carcinoma and growth inhibition by its agonists,” Biochemical and Biophysical Research Communications, vol. 287, no. 3, pp. 727–732, 2001. View at Publisher · View at Google Scholar · View at PubMed
  149. R. Mössner, U. Schulz, U. Krüger et al., “Agonists of peroxisome proliferator-activated receptor γ inhibit cell growth in malignant melanoma,” Journal of Investigative Dermatology, vol. 119, no. 3, pp. 576–582, 2002. View at Publisher · View at Google Scholar · View at PubMed
  150. T. Nijsten, E. Geluyckens, C. Colpaert, and J. Lambert, “Peroxisome proliterator-activated receptors in squamous cell carcinoma and its precursors,” Journal of Cutaneous Pathology, vol. 32, no. 5, pp. 340–347, 2005. View at Publisher · View at Google Scholar · View at PubMed
  151. T.-I. Jung, W.-K. Baek, S.-I. Suh et al., “Down-regulation of peroxisome proliferator-activated receptor gamma in human cervical carcinoma,” Gynecologic Oncology, vol. 97, no. 2, pp. 365–373, 2005. View at Publisher · View at Google Scholar · View at PubMed
  152. T. Hase, R. Yoshimura, M. Mitsuhashi et al., “Expression of peroxisome proliferator-activated receptors in human testicular cancer and growth inhibition by its agonists,” Urology, vol. 60, no. 3, pp. 542–547, 2002. View at Publisher · View at Google Scholar
  153. S. W. Han, M. E. Greene, J. Pitts, R. K. Wada, and N. Sidell, “Novel expression and function of peroxisome proliferator-activated receptor gamma (PPARγ) in human neuroblastoma cells,” Clinical Cancer Research, vol. 7, no. 1, pp. 98–104, 2001. View at Google Scholar
  154. A. P. Heaney, M. Fernando, W. H. Yong, and S. Melmed, “Functional PPAR-γ receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas,” Nature Medicine, vol. 8, no. 11, pp. 1281–1287, 2002. View at Publisher · View at Google Scholar · View at PubMed
  155. J.-A. Kim, K.-S. Park, H.-I. Kim et al., “Troglitazone activates p21Cip/WAF1 through the ERK pathway in HCT15 human colorectal cancer cells,” Cancer Letters, vol. 179, no. 2, pp. 185–195, 2002. View at Publisher · View at Google Scholar
  156. W.-L. Yang and H. Frucht, “Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells,” Carcinogenesis, vol. 22, no. 9, pp. 1379–1383, 2001. View at Publisher · View at Google Scholar
  157. T. Tanaka, H. Kohno, S. Yoshitani et al., “Ligands for peroxisome proliferator-activated receptors α and γ inhibit chemically induced colitis and formation of aberrant crypt foci in rats,” Cancer Research, vol. 61, no. 6, pp. 2424–2428, 2001. View at Google Scholar
  158. F. Yin, S. Wakino, Z. Liu et al., “Troglitazone inhibits growth of MCF-7 breast carcinoma cells by targeting G1 cell cycle regulators,” Biochemical and Biophysical Research Communications, vol. 286, no. 5, pp. 916–922, 2001. View at Publisher · View at Google Scholar · View at PubMed
  159. N. Suh, Y. Wang, C. R. Williams et al., “A new ligand for the peroxisome proliferator-activated receptor-γ (PPAR-γ), GW7845, inhibits rat mammary carcinogenesis,” Cancer Research, vol. 59, no. 22, pp. 5671–5673, 1999. View at Google Scholar
  160. C. E. Clay, A. M. Namen, G. Atsumi et al., “Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells,” Carcinogenesis, vol. 20, no. 10, pp. 1905–1911, 1999. View at Publisher · View at Google Scholar
  161. R. G. Mehta, E. Williamson, M. K. Patel, and H. P. Koeffler, “A ligand of peroxisome proliferator-activated receptor γ, retinoids, and prevention of preneoplastic mammary lesions,” Journal of the National Cancer Institute, vol. 92, no. 5, pp. 418–423, 2000. View at Publisher · View at Google Scholar
  162. E. Elstner, C. Müller, K. Koshizuka et al., “Ligands for peroxisome proliferator-activated receptorγ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 15, pp. 8806–8811, 1998. View at Publisher · View at Google Scholar
  163. C. Giacinti and A. Giordano, “RB and cell cycle progression,” Oncogene, vol. 25, no. 38, pp. 5220–5227, 2006. View at Publisher · View at Google Scholar · View at PubMed
  164. N. Takahashi, T. Okumura, W. Motomura, Y. Fujimoto, I. Kawabata, and Y. Kohgo, “Activation of PPARγ inhibits cell growth and induces apoptosis in human gastric cancer cells,” FEBS Letters, vol. 455, no. 1-2, pp. 135–139, 1999. View at Publisher · View at Google Scholar
  165. G. Eibl, M. N. Wente, H. A. Reber, and O. J. Hines, “Peroxisome proliferator-activated receptor γ induces pancreatic cancer cell apoptosis,” Biochemical and Biophysical Research Communications, vol. 287, no. 2, pp. 522–529, 2001. View at Publisher · View at Google Scholar · View at PubMed
  166. A. Itami, G. Watanabe, Y. Shimada et al., “Ligands for peroxisome proliferator-activated receptor γ inhibit growth of pancreatic cancers both in vitro and in vivo,” International Journal of Cancer, vol. 94, no. 3, pp. 370–376, 2001. View at Publisher · View at Google Scholar · View at PubMed
  167. 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
  168. M. A. K. Rumi, H. Sato, S. Ishihara et al., “Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma,” British Journal of Cancer, vol. 84, no. 12, pp. 1640–1647, 2001. View at Publisher · View at Google Scholar · View at PubMed
  169. M. Toyoda, H. Takagi, N. Horiguchi et al., “A ligand for peroxisome proliferator activated receptor γ inhibits cell growth and induces apoptosis in human liver cancer cells,” Gut, vol. 50, no. 4, pp. 563–567, 2002. View at Publisher · View at Google Scholar
  170. M. J. Betz, I. Shapiro, M. Fassnacht, S. Hahner, M. Reincke, and F. Beuschlein, “Peroxisome proliferator-activated receptor-γ agonists suppress adrenocortical tumor cell proliferation and induce differentiation,” Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 7, pp. 3886–3896, 2005. View at Publisher · View at Google Scholar · View at PubMed
  171. Y. Tsubouchi, H. Sano, Y. Kawahito et al., “Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-γ agonists through induction of apoptosis,” Biochemical and Biophysical Research Communications, vol. 270, no. 2, pp. 400–405, 2000. View at Publisher · View at Google Scholar · View at PubMed
  172. J. Hisatake, T. Ikezoe, M. Carey, S. Holden, S. Tomoyasu, and H. P. Koeffler, “Down-regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor γ in human prostate cancer,” Cancer Research, vol. 60, no. 19, pp. 5494–5498, 2000. View at Google Scholar
  173. 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. View at Google Scholar
  174. 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-APCMin/+ mice,” Nature Medicine, vol. 4, no. 9, pp. 1053–1057, 1998. View at Publisher · View at Google Scholar · View at PubMed
  175. 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. View at Publisher · View at Google Scholar · View at PubMed
  176. 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. View at Publisher · View at Google Scholar · View at PubMed
  177. E. Saez, J. Rosenfeld, A. Livolsi et al., “PPARγ signaling exacerbates mammary gland tumor development,” Genes & Development, vol. 18, no. 5, pp. 528–540, 2004. View at Publisher · View at Google Scholar · View at PubMed
  178. S. S. Palakurthi, H. Aktas, L. M. Grubissich, R. M. Mortensen, and J. A. Halperin, “Anticancer effects of thiazolidinediones are independent of peroxisome proliferator-activated receptor γ and mediated by inhibition of translation initiation,” Cancer Research, vol. 61, no. 16, pp. 6213–6218, 2001. View at Google Scholar
  179. P. Sertznig, M. Seifert, W. Tilgen, and J. Reichrath, “Present concepts and future outlook: function of peroxisome proliferator-activated receptors (PPARs) for pathogenesis, progression, and therapy of cancer,” Journal of Cellular Physiology, vol. 212, no. 1, pp. 1–12, 2007. View at Publisher · View at Google Scholar · View at PubMed
  180. J. M. Olefsky, “Treatment of insulin resistance with peroxisome proliferator-activated receptor γ agonists,” Journal of Clinical Investigation, vol. 106, no. 4, pp. 467–472, 2000. View at Publisher · View at Google Scholar · View at PubMed
  181. M. B. Sporn, N. Suh, and D. J. Mangelsdorf, “Prospects for prevention and treatment of cancer with selective PPARγ modulators (SPARMs),” Trends in Molecular Medicine, vol. 7, no. 9, pp. 395–400, 2001. View at Publisher · View at Google Scholar
  182. R. K. Ockner, J. A. Manning, R. B. Poppenhausen, and W. K. L. Ho, “A binding protein for fatty acids in cytosol of intestinal mucosa, liver, myocardium, and other tissues,” Science, vol. 177, no. 4043, pp. 56–58, 1972. View at Publisher · View at Google Scholar
  183. J. R. Cannon and P. I. Eacho, “Interaction of LY171883 and other peroxisome proliferators with fatty-acid-binding protein isolated from rat liver,” Biochemical Journal, vol. 280, no. 2, pp. 387–391, 1991. View at Google Scholar
  184. H. Huang, O. Starodub, A. McIntosh et al., “Liver fatty acid-binding protein colocalizes with peroxisome proliferator activated receptor α and enhances ligand distribution to nuclei of living cells,” Biochemistry, vol. 43, no. 9, pp. 2484–2500, 2004. View at Publisher · View at Google Scholar · View at PubMed
  185. C. Wolfrum, T. Börchers, J. C. Sacchettini, and F. Spener, “Binding of fatty acids and peroxisome proliferators to orthologous fatty acid binding proteins from human, murine, and bovine liver,” Biochemistry, vol. 39, no. 6, pp. 1469–1474, 2000. View at Publisher · View at Google Scholar
  186. A. Adida and F. Spener, “Adipocyte-type fatty acid-binding protein as inter-compartmental shuttle for peroxisome proliferator activated receptor γ agonists in cultured cell,” Biochimica et Biophysica Acta, vol. 1761, no. 2, pp. 172–181, 2006. View at Publisher · View at Google Scholar · View at PubMed
  187. T. T. Schug, D. C. Berry, N. S. Shaw, S. N. Travis, and N. Noy, “Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors,” Cell, vol. 129, no. 4, pp. 723–733, 2007. View at Publisher · View at Google Scholar · View at PubMed
  188. H. Huang, O. Starodub, A. McIntosh, A. B. Kier, and F. Schroeder, “Liver fatty acid-binding protein targets fatty acids to the nucleus. Real time confocal and multiphoton fluorescence imaging in living cells,” Journal of Biological Chemistry, vol. 277, no. 32, pp. 29139–29151, 2002. View at Publisher · View at Google Scholar · View at PubMed
  189. J. W. Lawrence, D. J. Kroll, and P. I. Eacho, “Ligand-dependent interaction of hepatic fatty acid-binding protein with the nucleus,” Journal of Lipid Research, vol. 41, no. 9, pp. 1390–1401, 2000. View at Google Scholar
  190. N.-S. Tan, N. S. Shaw, N. Vinckenbosch et al., “Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription,” Molecular and Cellular Biology, vol. 22, no. 14, pp. 5114–5127, 2002. View at Publisher · View at Google Scholar
  191. C. Wolfrum, C. M. Borrmann, T. Börchers, and F. Spener, “Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors α- and γ-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 5, pp. 2323–2328, 2001. View at Publisher · View at Google Scholar · View at PubMed
  192. T. Helledie, M. Antonius, R. V. Sørensen et al., “Lipid-binding proteins modulate ligand-dependent trans-activation by peroxisome proliferator-activated receptors and localize to the nucleus as well as the cytoplasm,” Journal of Lipid Research, vol. 41, no. 11, pp. 1740–1751, 2000. View at Google Scholar
  193. D. Dong, S. E. Ruuska, D. J. Levinthal, and N. Noy, “Distinct roles for cellular retinoic acid-binding proteins I and II in regulating signaling by retinoic acid,” Journal of Biological Chemistry, vol. 274, no. 34, pp. 23695–23698, 1999. View at Publisher · View at Google Scholar
  194. N. Shaw, M. Elholm, and N. Noy, “Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor β/δ,” Journal of Biological Chemistry, vol. 278, no. 43, pp. 41589–41592, 2003. View at Publisher · View at Google Scholar · View at PubMed
  195. M. A. Peraza, A. D. Burdick, H. E. Marin, F. J. Gonzalez, and J. M. Peters, “The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR),” Toxicological Sciences, vol. 90, no. 2, pp. 269–295, 2006. View at Publisher · View at Google Scholar · View at PubMed