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PPAR Research
Volume 2008, Article ID 103167, 14 pages
http://dx.doi.org/10.1155/2008/103167
Review Article

Rat Urinary Bladder Carcinogenesis by Dual-Acting PPAR Agonists

1Molecular Toxicology, Novo Nordisk A/S, 2760 Maalov, Denmark
2Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York, York YO10 5YW, UK
3Biopharm Toxicology and Safety Pharmacology, Novo Nordisk A/S, 2760 Maalov, Denmark

Received 14 August 2008; Accepted 7 October 2008

Academic Editor: Dipak Panigrahy

Copyright © 2008 Martin B. Oleksiewicz 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. J. P. Berger, T. E. Akiyama, and P. T. Meinke, “PPARs: therapeutic targets for metabolic disease,” Trends in Pharmacological Sciences, vol. 26, no. 5, pp. 244–251, 2005. View at Publisher · View at Google Scholar
  2. Z. Nahlé, “PPAR trilogy from metabolism to cancer,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 7, no. 4, pp. 397–402, 2004. View at Publisher · View at Google Scholar
  3. C. Fiévet, J.-C. Fruchart, and B. Staels, “PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome,” Current Opinion in Pharmacology, vol. 6, no. 6, pp. 606–614, 2006. View at Publisher · View at Google Scholar
  4. P. Balakumar, M. Rose, S. S. Ganti, P. Krishan, and M. Singh, “PPAR dual agonists: are they opening Pandora's Box?” Pharmacological Research, vol. 56, no. 2, pp. 91–98, 2007. View at Publisher · View at Google Scholar
  5. A. Rubenstrunk, R. Hanf, D. W. Hum, J.-C. Fruchart, and B. Staels, “Safety issues and prospects for future generations of PPAR modulators,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 1065–1081, 2007. View at Publisher · View at Google Scholar
  6. M. A. K. Rumi, S. Ishihara, H. Kazumori, Y. Kadowaki, and Y. Kinoshita, “Can PRARγ ligands be used in cancer therapy?” Current Medicinal Chemistry. Anti-Cancer Agents, vol. 4, no. 6, pp. 465–477, 2004. View at Publisher · View at Google Scholar
  7. D. Conlon, “Goodbye glitazars?” British Journal of Diabetes and Vascular Disease, vol. 6, no. 3, pp. 135–137, 2006. View at Publisher · View at Google Scholar
  8. J. El-Hage, “Preclinical and clinical safety assessments for PPAR agonists,” 2004, http://www.fda.gov/cder/present/DIA2004/Elhage.ppt.
  9. 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
  10. J. E. Klaunig, M. A. Babich, K. P. Baetcke et al., “PPARa agonist-induced rodent tumors: modes of action and human relevance,” Critical Reviews in Toxicology, vol. 33, no. 6, pp. 655–780, 2003. View at Publisher · View at Google Scholar
  11. E. M. Wulff, L. Jeppesen, P. S. Bury et al., “The anti-diabetic activity of the dual-acting PPARa/? agonist ragaglitazar: a comparative study with known insulin sensitizers in vitro and in vivo,” Diabetologia, vol. 45, supplement 2, p. 727, 2002. View at Google Scholar
  12. T. Ohnishi, L. L. Arnold, N. M. Clark, J. L. Wisecarver, and S. M. Cohen, “Comparison of endothelial cell proliferation in normal liver and adipose tissue in B6C3F1 mice, F344 rats, and humans,” Toxicologic Pathology, vol. 35, no. 7, pp. 904–909, 2007. View at Publisher · View at Google Scholar
  13. H. Hellmold, H. Zhang, U. Andersson et al., “Tesaglitazar, a PPARa/? agonist, induces interstitial mesenchymal cell DNA synthesis and fibrosarcomas in subcutaneous tissues in rats,” Toxicological Sciences, vol. 98, no. 1, pp. 63–74, 2007. View at Publisher · View at Google Scholar
  14. J. R. Herman, L. A. Dethloff, E. J. McGuire et al., “Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone,” Toxicological Sciences, vol. 68, no. 1, pp. 226–236, 2002. View at Publisher · View at Google Scholar
  15. L. Michalik, J. Auwerx, J. P. Berger et al., “International union of pharmacology. LXI. Peroxisome proliferator-activated receptors,” Pharmacological Reviews, vol. 58, no. 4, pp. 726–741, 2006. View at Publisher · View at Google Scholar
  16. P. Escher, O. Braissant, S. Basu-Modak, L. Michalik, W. Wahli, and B. Desvergne, “Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding,” Endocrinology, vol. 142, no. 10, pp. 4195–4202, 2001. View at Publisher · View at Google Scholar
  17. Y. Guan, Y. Zhang, L. Davis, and M. D. Breyer, “Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans,” American Journal of Physiology, vol. 273, no. 6, part 2, pp. F1013–F1022, 1997. View at Google Scholar
  18. B. Chopra, J. Hinley, M. B. Oleksiewicz, and J. Southgate, “Trans-species comparison of PPAR and RXR expression by rat and human urothelial tissues,” Toxicologic Pathology, vol. 36, no. 3, pp. 485–495, 2008. View at Publisher · View at Google Scholar
  19. C. De Ciuceis, F. Amiri, M. Iglarz, J. S. Cohn, R. M. Touyz, and E. L. Schiffrin, “Synergistic vascular protective effects of combined low doses of PPARα and PPARγ activators in angiotensin II-induced hypertension in rats,” British Journal of Pharmacology, vol. 151, no. 1, pp. 45–53, 2007. View at Publisher · View at Google Scholar
  20. R. M. Touyz and E. L. Schiffrin, “Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications,” Vascular Pharmacology, vol. 45, no. 1, pp. 19–28, 2006. View at Publisher · View at Google Scholar
  21. A. Mazzucotelli, N. Viguerie, C. Tiraby et al., “The transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)? coactivator-1a and the nuclear receptor PPARa control the expression of glycerol kinase and metabolism genes independently of PPAR? activation in human white adipocytes,” Diabetes, vol. 56, no. 10, pp. 2467–2475, 2007. View at Publisher · View at Google Scholar
  22. A. Vidal-Puig, M. Jimenez-Liñan, B. B. Lowell et al., “Regulation of PPAR ? gene expression by nutrition and obesity in rodents,” The Journal of Clinical Investigation, vol. 97, no. 11, pp. 2553–2561, 1996. View at Publisher · View at Google Scholar
  23. H.-I. Kim, Y.-K. Koh, T.-H. Kim et al., “Transcriptional activation of SHP by PPAR-? in liver,” Biochemical and Biophysical Research Communications, vol. 360, no. 2, pp. 301–306, 2007. View at Publisher · View at Google Scholar
  24. N. Viswakarma, S. Yu, S. Naik et al., “Transcriptional regulation of Cidea, mitochondrial cell death-inducing DNA fragmentation factor a-like effector A, in mouse liver by peroxisome proliferator-activated receptor a and ?,” The Journal of Biological Chemistry, vol. 282, no. 25, pp. 18613–18624, 2007. View at Publisher · View at Google Scholar
  25. M. S. Kim, T. R. Sweeney, J. K. Shigenaga et al., “Tumor necrosis factor and interleukin 1 decrease RXRa, PPARa, PPAR?, LXRa, and the coactivators SRC-1, PGC-1a, and PGC-1ß in liver cells,” Metabolism: Clinical and Experimental, vol. 56, no. 2, pp. 267–279, 2007. View at Publisher · View at Google Scholar
  26. B. Lanne, B. Dahllöf, C. Lindahl et al., “PPARa and PPAR? regulation of liver and adipose proteins in obese and dyslipidemic rodents,” Journal of Proteome Research, vol. 5, no. 8, pp. 1850–1859, 2006. View at Publisher · View at Google Scholar
  27. C. R. Waites, M. A. Dominick, T. P. Sanderson, and B. E. Schilling, “Nonclinical safety evaluation of muraglitazar, a novel PPARα/γ agonist,” Toxicological Sciences, vol. 100, no. 1, pp. 248–258, 2007. View at Publisher · View at Google Scholar
  28. F. L. Egerod, H. S. Nielsen, L. Iversen, I. Thorup, T. Storgaard, and M. B. Oleksiewicz, “Biomarkers for early effects of carcinogenic dual-acting PPAR agonists in rat urinary bladder urothelium in vivo,” Biomarkers, vol. 10, no. 4, pp. 295–309, 2005. View at Publisher · View at Google Scholar
  29. B. S. Lima, M. Dominick, L. Iversen, and M. B. Oleksiewicz, “Peroxisome proliferators activated receptors (PPARs) agonists and rodent tumorigenesis: updating the discussions,” in Proceedings of the 42nd DIA Annual Meeting, Philadelphia, Pa, USA, June 2006, BT Biotechnology/ NC Nonclinical Labaroratory Safety 299D.
  30. M. B. Oleksiewicz, I. Thorup, H. S. Nielsen et al., “Generalized cellular hypertrophy is induced by a dual-acting PPAR agonist in rat urinary bladder urothelium in vivo,” Toxicologic Pathology, vol. 33, no. 5, pp. 552–560, 2005. View at Publisher · View at Google Scholar
  31. G. G. Long, V. L. Reynolds, A. Lopez-Martinez, T. E. Ryan, S. L. White, and S. R. Eldridge, “Urothelial carcinogenesis in the urinary bladder of rats treated with naveglitazar, a γ-dominant PPAR α/γ agonist: lack of evidence for urolithiasis as an inciting event,” Toxicologic Pathology, vol. 36, no. 2, pp. 218–231, 2008. View at Publisher · View at Google Scholar
  32. 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
  33. 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
  34. D. Panigrahy, S. Huang, M. W. Kieran, and A. Kaipainen, “PPARγ as a therapeutic target for tumor angiogenesis and metastasis,” Cancer Biology and Therapy, vol. 4, no. 7, pp. 687–693, 2005. View at Google Scholar
  35. A. Kaipainen, M. W. Kieran, S. Huang et al., “PPARa deficiency in inflammatory cells suppresses tumor growth,” PLoS ONE, vol. 2, no. 2, article e260, pp. 1–11, 2007. View at Publisher · View at Google Scholar
  36. A. Jain and D. B. Agus, “PPARγ signaling: one size fits all?” Cell Cycle, vol. 3, no. 11, pp. 1352–1354, 2004. View at Google Scholar
  37. V. G. Keshamouni, S. Han, and J. Roman, “Peroxisome proliferator-activated receptors in lung cancer,” PPAR Research, vol. 2007, Article ID 90289, 10 pages, 2007. View at Publisher · View at Google Scholar
  38. S. Jain, S. Pulikuri, Y. Zhu et al., “Differential expression of the peroxisome proliferator-activated receptor ? (PPAR?) and its coactivators steroid receptor coactivator-1 and PPAR-binding protein PBP in the brown fat, urinary bladder, colon, and breast of the mouse,” American Journal of Pathology, vol. 153, no. 2, pp. 349–354, 1998. View at Google Scholar
  39. J. Stahlschmidt, C. L. Varley, G. Toogood, P. J. Selby, and J. Southgate, “Urothelial differentiation in chronically urine-deprived bladders of patients with end-stage renal disease,” Kidney International, vol. 68, no. 3, pp. 1032–1040, 2005. View at Publisher · View at Google Scholar
  40. C. L. Varley, J. Stahlschmidt, B. Smith, M. Stower, and J. Southgate, “Activation of peroxisome proliferator-activated receptor-γ reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells,” American Journal of Pathology, vol. 164, no. 5, pp. 1789–1798, 2004. View at Google Scholar
  41. K.-I. Nakashiro, Y. Hayashi, A. Kita et al., “Role of peroxisome proliferator-activated receptor ? and its ligands in non-neoplastic and neoplastic human urothelial cells,” American Journal of Pathology, vol. 159, no. 2, pp. 591–597, 2001. View at Google Scholar
  42. J. Southgate, K. A. Hutton, D. F. Thomas, and L. K. Trejdosiewicz, “Normal human urothelial cells in vitro: proliferation and induction of stratification,” Laboratory Investigation, vol. 71, no. 4, pp. 583–594, 1994. View at Google Scholar
  43. R. A. Crallan, N. T. Georgopoulos, and J. Southgate, “Experimental models of human bladder carcinogenesis,” Carcinogenesis, vol. 27, no. 3, pp. 374–381, 2006. View at Publisher · View at Google Scholar
  44. C. L. Varley, J. Stahlschmidt, W.-C. Lee et al., “Role of PPAR ? and EGFR signalling in the urothelial terminal differentiation programme,” Journal of Cell Science, vol. 117, no. 10, pp. 2029–2036, 2004. View at Publisher · View at Google Scholar
  45. C. L. Varley, M. A. E. Garthwaite, W. Cross, J. Hinley, L. K. Trejdosiewicz, and J. Southgate, “PPARγ-regulated tight junction development during human urothelial cytodifferentiation,” Journal of Cellular Physiology, vol. 208, no. 2, pp. 407–417, 2006. View at Publisher · View at Google Scholar
  46. C. L. Varley, E. J. Bacon, J. C. Holder, and J. Southgate, “FOXA1 and IRF-1 intermediary transcriptional regulators of PPARγ-induced urothelial cytodifferentiation,” Cell Death & Differentiation, vol. 16, no. 1, pp. 103–114, 2008. View at Publisher · View at Google Scholar
  47. C. Varley, G. Hill, S. Pellegrin et al., “Autocrine regulation of human urothelial cell proliferation and migration during regenerative responses in vitro,” Experimental Cell Research, vol. 306, no. 1, pp. 216–229, 2005. View at Publisher · View at Google Scholar
  48. S. M. Cohen, “Effects of PPARγ and combined agonists on the urinary tract of rats and other species,” Toxicological Sciences, vol. 87, no. 2, pp. 322–327, 2005. View at Publisher · View at Google Scholar
  49. R. A. Lubet, S. M. Fischer, V. E. Steele, M. M. Juliana, R. Desmond, and C. J. Grubbs, “Rosiglitazone, a PPAR gamma agonist: potent promoter of hydroxybutyl(butyl)nitrosamine-induced urinary bladder cancers,” International Journal of Cancer, vol. 123, no. 10, pp. 2254–2259, 2008. View at Publisher · View at Google Scholar
  50. K. A. Hutton, L. K. Trejdosiewicz, D. F. Thomas, and J. Southgate, “Urothelial tissue culture for bladder reconstruction: an experimental study,” The Journal of Urology, vol. 150, no. 2, part 2, pp. 721–725, 1993. View at Google Scholar
  51. S. Fauconnet, I. Lascombe, E. Chabannes et al., “Differential regulation of vascular endothelial growth factor expression by peroxisome proliferator-activated receptors in bladder cancer cells,” The Journal of Biological Chemistry, vol. 277, no. 26, pp. 23534–23543, 2002. View at Publisher · View at Google Scholar
  52. A. Hagiwara, S. Tamano, T. Ogiso, E. Asakawa, and S. Fukushima, “Promoting effect of the peroxisome proliferator, clofibrate, but not di(2-ethylhexyl)phthalate, on urinary bladder carcinogenesis in F344 rats initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine,” Japanese Journal of Cancer Research, vol. 81, no. 12, pp. 1232–1238, 1990. View at Google Scholar
  53. X. Zuo, Y. Wu, J. S. Morris et al., “Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity,” Oncogene, vol. 25, no. 8, pp. 1225–1241, 2006. View at Publisher · View at Google Scholar
  54. M. Mensink, M. K. C. Hesselink, A. P. Russell, G. Schaart, J.-P. Sels, and P. Schrauwen, “Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1α and PPARβ/δ gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus,” International Journal of Obesity, vol. 31, no. 8, pp. 1302–1310, 2007. View at Publisher · View at Google Scholar
  55. M. Rose, P. Balakumar, and M. Singh, “Ameliorative effect of combination of fenofibrate and rosiglitazone in pressure overload-induced cardiac hypertrophy in rats,” Pharmacology, vol. 80, no. 2-3, pp. 177–184, 2007. View at Publisher · View at Google Scholar
  56. B. B. Lohray, V. B. Lohray, A. C. Bajji et al., “(-)3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid [(-)DRF 2725]: a dual PPAR agonist with potent antihyperglycemic and lipid modulating activity,” Journal of Medicinal Chemistry, vol. 44, no. 16, pp. 2675–2678, 2001. View at Publisher · View at Google Scholar
  57. S. Ebdrup, I. Pettersson, H. B. Rasmussen et al., “Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor a/? agonist ragaglitazar,” Journal of Medicinal Chemistry, vol. 46, no. 8, pp. 1306–1317, 2003. View at Publisher · View at Google Scholar
  58. J. A. Davies, A. D. Perera, and C. L. Walker, “Mechanisms of epithelial development and neoplasia in the metanephric kidney,” International Journal of Developmental Biology, vol. 43, no. 5, pp. 473–478, 1999. View at Google Scholar
  59. I. Riedel, F.-X. Liang, F.-M. Deng et al., “Urothelial umbrella cells of human ureter are heterogeneous with respect to their uroplakin composition: different degrees of urothelial maturity in ureter and bladder?” European Journal of Cell Biology, vol. 84, no. 2-3, pp. 393–405, 2005. View at Publisher · View at Google Scholar
  60. M. Jhamb, J. Lin, R. Ballow, A. M. Kamat, H. B. Grossman, and X. Wu, “Urinary tract diseases and bladder cancer risk: a case-control study,” Cancer Causes & Control, vol. 18, no. 8, pp. 839–845, 2007. View at Publisher · View at Google Scholar
  61. B. Chopra, N. T. Georgopoulos, A. Nicholl, J. Hinley, M. B. Oleksiewicz, and J. Southgate, “Non-genomic cytotoxicity of structurally diverse PPAR agonists in normal human urothelial cells in vitro,” accepted, 2009, Cell Proliferation.
  62. O. S. Gardner, B. J. Dewar, and L. M. Graves, “Activation of mitogen-activated protein kinases by peroxisome proliferator-activated receptor ligands: an example of nongenomic signaling,” Molecular Pharmacology, vol. 68, no. 4, pp. 933–941, 2005. View at Publisher · View at Google Scholar
  63. R. G. Croy, “Role of chemically induced cell proliferation in carcinogenesis and its use in health risk assessment,” Environmental Health Perspectives, vol. 101, supplement 5, pp. 289–302, 1993. View at Publisher · View at Google Scholar
  64. L. Tomatis, “Cell proliferation and carcinogenesis: a brief history and current view based on an IARC workshop report,” Environmental Health Perspectives, vol. 101, supplement 5, pp. 149–151, 1993. View at Publisher · View at Google Scholar
  65. M. Hartl, A. G. Bader, and K. Bister, “Molecular targets of the oncogenic transcription factor jun,” Current Cancer Drug Targets, vol. 3, no. 1, pp. 41–55, 2003. View at Publisher · View at Google Scholar
  66. M. I. Luster and P. P. Simeonova, “Arsenic and urinary bladder cell proliferation,” Toxicology and Applied Pharmacology, vol. 198, no. 3, pp. 419–423, 2004. View at Publisher · View at Google Scholar
  67. P. P. Simeonova, S. Wang, W. Toriuma et al., “Arsenic mediates cell proliferation and gene expression in the bladder epithelium: association with activating protein-1 transactivation,” Cancer Research, vol. 60, no. 13, pp. 3445–3453, 2000. View at Google Scholar
  68. G. Thiel and G. Cibelli, “Regulation of life and death by the zinc finger transcription factor Egr-1,” Journal of Cellular Physiology, vol. 193, no. 3, pp. 287–292, 2002. View at Publisher · View at Google Scholar
  69. L. M. Khachigian, “Early growth response-1: blocking angiogenesis by shooting the messenger,” Cell Cycle, vol. 3, no. 1, pp. 10–11, 2004. View at Google Scholar
  70. Y. Levkovitz and J. M. Baraban, “A dominant negative Egr inhibitor blocks nerve growth factor-induced neurite outgrowth by suppressing c-Jun activation: role of an Egr/c-Jun complex,” Journal of Neuroscience, vol. 22, no. 10, pp. 3845–3854, 2002. View at Google Scholar
  71. S. L. Lee, Y. Sadovsky, A. H. Swirnoff et al., “Luteinizing hormone deficiency and female infertility in mice lacking the transcription factor NGFI-A (Egr-1),” Science, vol. 273, no. 5279, pp. 1219–1221, 1996. View at Publisher · View at Google Scholar
  72. F. J. Rauscher III, J. F. Morris, O. E. Tournay, D. M. Cook, and T. Curran, “Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence,” Science, vol. 250, no. 4985, pp. 1259–1262, 1990. View at Publisher · View at Google Scholar
  73. M. A. Ghanem, T. H. van der Kwast, J. C. Den Hollander et al., “Expression and prognostic value of Wilms' tumor 1 and early growth response 1 proteins in nephroblastoma,” Clinical Cancer Research, vol. 6, no. 11, pp. 4265–4271, 2000. View at Google Scholar
  74. V. Scharnhorst, A. L. Menke, J. Attema et al., “EGR-1 enhances tumor growth and modulates the effect of the Wilms' tumor 1 gene products on tumorigenicity,” Oncogene, vol. 19, no. 6, pp. 791–800, 2000. View at Publisher · View at Google Scholar
  75. R. R. Rackley, P. M. Kessler, C. Campbell, and B. R. G. Williams, “In situ expression of the early growth response gene-1 during murine nephrogenesis,” The Journal of Urology, vol. 154, no. 2, pp. 700–705, 1995. View at Publisher · View at Google Scholar
  76. D. M. Cohen, “Urea-inducible Egr-1 transcription in renal inner medullary collecting duct (mIMCD3) cells is mediated by extracellular signal-regulated kinase activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 20, pp. 11242–11247, 1996. View at Publisher · View at Google Scholar
  77. M. R. Saban, H. Hellmich, N. B. Nguyen, J. Winston, T. G. Hammond, and R. Saban, “Time course of LPS-induced gene expression in a mouse model of genitourinary inflammation,” Physiol Genomics, vol. 5, no. 3, pp. 147–160, 2001. View at Google Scholar
  78. R. Saban, C. Simpson, R. Vadigepalli, S. Memet, I. Dozmorov, and M. R. Saban, “Bladder inflammatory transcriptome in response to tachykinins: neurokinin 1 receptor-dependent genes and transcription regulatory elements,” BMC Urology, vol. 7, article 7, pp. 1–17, 2007. View at Publisher · View at Google Scholar
  79. W. Wei, P. S. Howard, B. Kogan, and E. J. Macarak, “Altered extracellular matrix expression in the diverted fetal sheep bladder,” The Journal of Urology, vol. 178, no. 3, pp. 1104–1107, 2007. View at Publisher · View at Google Scholar
  80. K. Saito, S. Kawakami, Y. Okada et al., “Spatial and isoform specific p63 expression in the male human urogenital tract,” The Journal of Urology, vol. 176, no. 5, pp. 2268–2273, 2006. View at Publisher · View at Google Scholar
  81. S. Signoretti, M. M. Pires, M. Lindauer et al., “p63 regulates commitment to the prostate cell lineage,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 32, pp. 11355–11360, 2005. View at Publisher · View at Google Scholar
  82. S. A. Abdulkadir, “Mechanisms of prostate tumorigenesis: roles for transcription factors Nkx3.1 and Egr1,” Annals of the New York Academy of Sciences, vol. 1059, pp. 33–40, 2005. View at Google Scholar
  83. S. A. Abdulkadir, Z. Qu, E. Garabedian et al., “Impaired prostate tumorigenesis in Egr1-deficient mice,” Nature Medicine, vol. 7, no. 1, pp. 101–107, 2001. View at Publisher · View at Google Scholar
  84. Z. Salah, M. Maoz, G. Pizov, and R. Bar-Shavit, “Transcriptional regulation of human protease-activated receptor 1: a role for the early growth response-1 protein in prostate cancer,” Cancer Research, vol. 67, no. 20, pp. 9835–9843, 2007. View at Publisher · View at Google Scholar
  85. T.-S. Van Le, J. Myers, B. R. Konety, T. Barder, and R. H. Getzenberg, “Functional characterization of the bladder cancer marker, BLCA-4,” Clinical Cancer Research, vol. 10, no. 4, pp. 1384–1391, 2004. View at Publisher · View at Google Scholar
  86. M. E. Nielsen, M. L. Gonzalgo, M. P. Schoenberg, and R. H. Getzenberg, “Toward critical evaluation of the role(s) of molecular biomarkers in the management of bladder cancer,” World Journal of Urology, vol. 24, no. 5, pp. 499–508, 2006. View at Publisher · View at Google Scholar
  87. J. Faridi, J. Fawcett, L. Wang, and R. A. Roth, “Akt promotes increased mammalian cell size by stimulating protein synthesis and inhibiting protein degradation,” American Journal of Physiology, vol. 285, no. 5, pp. E964–E972, 2003. View at Google Scholar
  88. E. C. Holland, N. Sonenberg, P. P. Pandolfi, and G. Thomas, “Signaling control of mRNA translation in cancer pathogenesis,” Oncogene, vol. 23, no. 18, pp. 3138–3144, 2004. View at Publisher · View at Google Scholar
  89. E. C. Holland, “Regulation of translation and cancer,” Cell Cycle, vol. 3, no. 4, pp. 452–455, 2004. View at Google Scholar
  90. E. Petroulakis, Y. Mamane, O. Le Bacquer, D. Shahbazian, and N. Sonenberg, “mTOR signaling: implications for cancer and anticancer therapy,” British Journal of Cancer, vol. 94, no. 2, pp. 195–199, 2006. View at Publisher · View at Google Scholar
  91. J. Montagne, M. J. Stewart, H. Stocker, E. Hafen, S. C. Kozma, and G. Thomas, “Drosophila S6 kinase: a regulator of cell size,” Science, vol. 285, no. 5436, pp. 2126–2129, 1999. View at Publisher · View at Google Scholar
  92. H. Shima, M. Pende, Y. Chen, S. Fumagalli, G. Thomas, and S. C. Kozma, “Disruption of the p705s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase,” The EMBO Journal, vol. 17, no. 22, pp. 6649–6659, 1998. View at Google Scholar
  93. A. G. Bader, S. Kang, L. Zhao, and P. K. Vogt, “Oncogenic PI3K deregulates transcription and translation,” Nature Reviews Cancer, vol. 5, no. 12, pp. 921–929, 2005. View at Publisher · View at Google Scholar
  94. S. Molon-Noblot, C. Boussiquet-Leroux, R. A. Owen et al., “Rat urinary bladder hyperplasia induced by oral administration of carbonic anhydrase inhibitors,” Toxicologic Pathology, vol. 20, no. 1, pp. 93–102, 1992. View at Google Scholar
  95. T. A. Lawson, K. M. Dawson, and D. B. Clayson, “Acute changes in nucleic acid and protein synthesis in the mouse bladder epithelium induced by three bladder carcinogens,” Cancer Research, vol. 30, no. 6, pp. 1586–1592, 1970. View at Google Scholar
  96. D. C. Fingar and J. Blenis, “Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression,” Oncogene, vol. 23, no. 18, pp. 3151–3171, 2004. View at Publisher · View at Google Scholar
  97. O. S. Gardner, C.-W. Shiau, C.-S. Chen, and L. M. Graves, “Peroxisome proliferator-activated receptor γ-independent activation of p38 MAPK by thiazolidinediones involves calcium/calmodulin-dependent protein kinase II and protein kinase R: correlation with endoplasmic reticulum stress,” The Journal of Biological Chemistry, vol. 280, no. 11, pp. 10109–10118, 2005. View at Publisher · View at Google Scholar
  98. B. J. Dewar, O. S. Gardner, C.-S. Chen, H. S. Earp, J. M. Samet, and L. M. Graves, “Capacitative calcium entry contributes to the differential transactivation of the epidermal growth factor receptor in response to thiazolidinediones,” Molecular Pharmacology, vol. 72, no. 5, pp. 1146–1156, 2007. View at Publisher · View at Google Scholar
  99. R. Lösel and M. Wehling, “Nongenomic actions of steroid hormones,” Nature Reviews Molecular Cell Biology, vol. 4, no. 1, pp. 46–56, 2003. View at Publisher · View at Google Scholar
  100. I. K. Choi, Y. H. Kim, J. S. Kim, and J. H. Seo, “PPAR-γ ligand promotes the growth of APC-mutated HT-29 human colon cancer cells in vitro and in vivo,” Investigational New Drugs, vol. 26, no. 3, pp. 283–288, 2008. View at Publisher · View at Google Scholar
  101. E. Lucarelli, L. Sangiorgi, V. Maini et al., “Troglitazione affects survival of human osteosarcoma cells,” International Journal of Cancer, vol. 98, no. 3, pp. 344–351, 2002. View at Publisher · View at Google Scholar
  102. Y. L. Wang, K. A. Frauwirth, S. M. Rangwala, M. A. Lazar, and C. B. Thompson, “Thiazolidinedione activation of peroxisome proliferator-activated receptor γ can enhance mitochondrial potential and promote cell survival,” The Journal of Biological Chemistry, vol. 277, no. 35, pp. 31781–31788, 2002. View at Publisher · View at Google Scholar
  103. C. E. Clay, A. M. Namen, G.-I. Atsumi et al., “Magnitude of peroxisome proliferator-activated receptor-? activation is associated with important and seemingly opposite biological responses in breast cancer cells,” Journal of Investigative Medicine, vol. 49, no. 5, pp. 413–420, 2001. View at Publisher · View at Google Scholar
  104. P. A. Spencer, C. L. Varley, J. C. Holder, W. J. Cairns, and J. Southgate, “Cytostasis of normal human urothelial cell lines by PPARgamma agonists is independent of PPARgamma activation,” in preparation.
  105. J. Southgate, E. Pitt, and L. K. Trejdosiewicz, “The effects of dietary fatty acids on the proliferation of normal human urothelial cells in vitro,” British Journal of Cancer, vol. 74, no. 5, pp. 728–734, 1996. View at Google Scholar
  106. N. A. Abumrad, “The PPAR balancing act,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 7, no. 4, pp. 367–368, 2004. View at Publisher · View at Google Scholar
  107. 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
  108. H. M. Mattern, P. G. Lloyd, M. Sturek, and C. D. Hardin, “Gender and genetic differences in bladder smooth muscle PPAR mRNA in a porcine model of the metabolic syndrome,” Molecular and Cellular Biochemistry, vol. 302, no. 1-2, pp. 43–49, 2007. View at Publisher · View at Google Scholar
  109. H. Lu, X. Lei, and C. Klaassen, “Gender differences in renal nuclear receptors and aryl hydrocarbon receptor in 5/6 nephrectomized rats,” Kidney International, vol. 70, no. 11, pp. 1920–1928, 2006. View at Publisher · View at Google Scholar
  110. E. Sanguino, R. Bejarano, M. Alegret, R. M. Sánchez, M. Vázquez-Carrera, and J. C. Laguna, “Sexual dimorphism in lipid metabolic phenotype associated with old age in Sprague-Dawley rats,” Experimental Gerontology, vol. 39, no. 9, pp. 1295–1306, 2004. View at Publisher · View at Google Scholar
  111. E. Rodríguez, J. Ribot, A. M. Rodríguez, and A. Palou, “PPAR-γ2 expression in response to cafeteria diet: gender- and depot-specific effects,” Obesity Research, vol. 12, no. 9, pp. 1455–1463, 2004. View at Publisher · View at Google Scholar
  112. M. Jalouli, L. Carlsson, C. Améen et al., “Sex difference in hepatic peroxisome proliferator-activated receptor a expression: influence of pituitary and gonadal hormones,” Endocrinology, vol. 144, no. 1, pp. 101–109, 2003. View at Publisher · View at Google Scholar
  113. A. J. Vidal-Puig, R. V. Considine, M. Jimenez-Liñan et al., “Peroxisome proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss, and regulation by insulin and glucocorticoids,” The Journal of Clinical Investigation, vol. 99, no. 10, pp. 2416–2422, 1997. View at Publisher · View at Google Scholar
  114. M. A. Dominick, M. R. White, T. P. Sanderson et al., “Urothelial carcinogenesis in the urinary bladder of male rats treated with muraglitazar, a PPARa/? agonist: evidence for urolithiasis as the inciting event in the mode of action,” Toxicologic Pathology, vol. 34, no. 7, pp. 903–920, 2006. View at Publisher · View at Google Scholar
  115. T. R. Van Vleet, M. R. White, T. P. Sanderson et al., “Subchronic urinary bladder effects of muraglitazar in male rats,” Toxicological Sciences, vol. 96, no. 1, pp. 58–71, 2007. View at Publisher · View at Google Scholar
  116. J. Nishiu, M. Ito, Y. Ishida et al., “JTP-426467 acts as a selective antagonist for peroxisome proliferator-activated receptor ? in vitro and in vivo,” Diabetes, Obesity & Metabolism, vol. 8, no. 5, pp. 508–516, 2006. View at Publisher · View at Google Scholar
  117. H. E. Xu, T. B. Stanley, V. G. Montana et al., “Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARa,” Nature, vol. 415, no. 6873, pp. 813–817, 2002. View at Publisher · View at Google Scholar
  118. N. Ramesh, B. Memarzadeh, Y. Ge et al., “Identification of pretreatment agents to enhance adenovirus infection of bladder epithelium,” Molecular Therapy, vol. 10, no. 4, pp. 697–705, 2004. View at Publisher · View at Google Scholar
  119. D. A. Bushinsky, M. J. Favus, A. B. Schneider, P. K. Sen, L. M. Sherwood, and F. L. Coe, “Effects of metabolic acidosis on PTH and 1,25(OH)2D3 response to low calcium diet,” American Journal of Physiology, vol. 243, no. 6, pp. F570–F575, 1982. View at Google Scholar
  120. E. S. C. Kwok and D. A. Eastmond, “Effects of pH on nonenzymatic oxidation of phenylhydroquinone: potential role in urinary bladder carcinogenesis induced by o-phenylphenol in Fischer 344 rats,” Chemical Research in Toxicology, vol. 10, no. 7, pp. 742–749, 1997. View at Publisher · View at Google Scholar
  121. T. Fujii, K. Nakamura, and K. Hiraga, “Effects of pH on the carcinogenicity of o-phenylphenol and sodium o-phenylphenate in the rat urinary bladder,” Food and Chemical Toxicology, vol. 25, no. 5, pp. 359–362, 1987. View at Publisher · View at Google Scholar
  122. M. K. St. John, L. L. Arnold, T. Anderson, M. Cano, S. L. Johansson, and S. M. Cohen, “Dietary effects of ortho-phenylphenol and sodium ortho-phenylphenate on rat urothelium,” Toxicological Sciences, vol. 59, no. 2, pp. 346–351, 2001. View at Publisher · View at Google Scholar
  123. A. P. de Groot, B. A. R. Lina, A. J. M. Hagenaars, V. M. H. Hollanders, M. Andringa, and V. J. Feron, “Effects of a dietary load of acid or base on changes induced by lactose in rats,” Food and Chemical Toxicology, vol. 33, no. 1, pp. 1–14, 1995. View at Publisher · View at Google Scholar
  124. A. P. de Groot, V. J. Feron, and H. R. Immel, “Induction of hyperplasia in the bladder epithelium of rats by a dietary excess of acid or base: implications for toxicity/carcinogenicity testing,” Food and Chemical Toxicology, vol. 26, no. 5, pp. 425–434, 1988. View at Publisher · View at Google Scholar
  125. S. H. Cha, J. E. Park, J.-O. Kwak et al., “Attenuation of extracellular acidic pH-induced cyclooxygenase-2 expression by nitric oxide,” Molecules and Cells, vol. 19, no. 2, pp. 232–238, 2005. View at Google Scholar
  126. K. Parczyk and C. Kondor-Koch, “The influence of pH on the vesicular traffic to the surface of the polarized epithelial cell, MDCK,” European Journal of Cell Biology, vol. 48, no. 2, pp. 353–359, 1989. View at Google Scholar
  127. M. Camacho, J. D. Machado, M. S. Montesinos, M. Criado, and R. Borges, “Intragranular pH rapidly modulates exocytosis in adrenal chromaffin cells,” Journal of Neurochemistry, vol. 96, no. 2, pp. 324–334, 2006. View at Publisher · View at Google Scholar
  128. M. S. Klempner and B. Styrt, “Alkalinizing the intralysosomal pH inhibits degranulation of human neutrophils,” The Journal of Clinical Investigation, vol. 72, no. 5, pp. 1793–1800, 1983. View at Publisher · View at Google Scholar
  129. N. Charoenphandhu, K. Wongdee, K. Tudpor, J. Pandaranandaka, and N. Krishnamra, “Chronic metabolic acidosis upregulated claudin mRNA expression in the duodenal enterocytes of female rats,” Life Sciences, vol. 80, no. 19, pp. 1729–1737, 2007. View at Publisher · View at Google Scholar
  130. W. E. Achanzar, C. F. Moyer, L. T. Marthaler et al., “Urine acidification has no effect on peroxisome proliferator-activated receptor (PPAR) signaling or epidermal growth factor (EGF) expression in rat urinary bladder urothelium,” Toxicology and Applied Pharmacology, vol. 223, no. 3, pp. 246–256, 2007. View at Publisher · View at Google Scholar
  131. E. Friday, R. Oliver III, T. Welbourne, and F. Turturro, “Role of epidermal growth factor receptor (EGFR)-signaling versus cellular acidosis via Na+/H+ exchanger1(NHE1)-inhibition in troglitazone-induced growth arrest of breast cancer-derived cells MCF-7,” Cellular Physiology and Biochemistry, vol. 20, no. 6, pp. 751–762, 2007. View at Publisher · View at Google Scholar
  132. F. Turturro, E. Friday, R. Fowler, D. Surie, and T. Welbourne, “Troglitazone acts on cellular pH and DNA synthesis through a peroxisome proliferator-activated receptor γ-independent mechanism in breast cancer-derived cell lines,” Clinical Cancer Research, vol. 10, no. 20, pp. 7022–7030, 2004. View at Publisher · View at Google Scholar
  133. T. Welbourne, G. Su, G. Coates, and R. Routh, “Troglitazone induces a cellular acidosis by inhibiting acid extrusion in cultured rat mesangial cells,” American Journal of Physiology, vol. 282, no. 6, pp. R1600–R1607, 2002. View at Google Scholar
  134. G. Coates, I. Nissim, H. Battarbee, and T. Welbourne, “Glitazones regulate glutamine metabolism by inducing a cellular acidosis in MDCK cells,” American Journal of Physiology, vol. 283, no. 4, pp. E729–E737, 2002. View at Google Scholar
  135. J. M. Brophy, “Selling safety—lessons from muraglitazar,” The Journal of the American Medical Association, vol. 294, no. 20, pp. 2633–2635, 2005. View at Publisher · View at Google Scholar
  136. H. Yki-Järvinen, “The PROactive study: some answers, many questions,” The Lancet, vol. 366, no. 9493, pp. 1241–1242, 2005. View at Publisher · View at Google Scholar