Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2008 (2008), Article ID 286249, 9 pages
http://dx.doi.org/10.1155/2008/286249
Review Article

The Role of NF- B in PPAR -Mediated Hepatocarcinogenesis

1Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
2College of Health and Human Services, Western Kentucky University, Bowling Green, KY 42101, USA
3Applied Biosystems, Foster City, CA 94404, USA
4Division of Transplant Surgery, Kidney Disease Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
5Food and Drug Administration, CFSAN/OFAS/DFCN, College Park, MD 20740, USA
6Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA

Received 30 May 2008; Revised 3 October 2008; Accepted 3 November 2008

Academic Editor: Dipak Panigrahy

Copyright © 2008 Howard P. Glauert 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. M. S. Rao and J. K. Reddy, “Peroxisome proliferation and hepatocarcinogenesis,” Carcinogenesis, vol. 8, no. 5, pp. 631–636, 1987. View at Publisher · View at Google Scholar
  2. R. C. Cattley, J. DeLuca, C. Elcombe et al., “Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans?” Regulatory Toxicology and Pharmacology, vol. 27, no. 1, pp. 47–60, 1998. View at Publisher · View at Google Scholar
  3. 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
  4. 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
  5. P. I. Eacho and D. R. Feller, “Hepatic peroxisome proliferation induced by hypolipidemic drugs and other chemicals,” in Antilipidemic Drugs, Medicinal, Chemical and Biochemical Aspects, D. T. Witiak, H. A. I. Newman, and D. R. Feller, Eds., pp. 375–426, Elsevier Science, Amsterdam, The Netherlands, 1991. View at Google Scholar
  6. E. A. Lock, A. M. Mitchell, and C. R. Elcombe, “Biochemical mechanisms of induction of hepatic peroxisome proliferation,” Annual Review of Pharmacology and Toxicology, vol. 29, pp. 145–163, 1989. View at Publisher · View at Google Scholar
  7. M. L. O'Brien, B. T. Spear, and H. P. Glauert, “Role of oxidative stress in peroxisome proliferator-mediated carcinogenesis,” Critical Reviews in Toxicology, vol. 35, no. 1, pp. 61–88, 2005. View at Publisher · View at Google Scholar
  8. M. Karin and A. Lin, “NF-κB at the crossroads of life and death,” Nature Immunology, vol. 3, no. 3, pp. 221–227, 2002. View at Publisher · View at Google Scholar
  9. M. Karin and M. Delhase, “The IκB kinase (IKK) and NF-κB: key elements of proinflammatory signalling,” Seminars in Immunology, vol. 12, no. 1, pp. 85–98, 2000. View at Publisher · View at Google Scholar
  10. E. Zandi, D. M. Rothwarf, M. Delhase, M. Hayakawa, and M. Karin, “The IκB kinase complex (IKK) contains two kinase subunits, IKKα and IKKβ, necessary for IκB phosphorylation and NF-κB activation,” Cell, vol. 91, no. 2, pp. 243–252, 1997. View at Publisher · View at Google Scholar
  11. M. Karin, “NF-κB and cancer: mechanisms and targets,” Molecular Carcinogenesis, vol. 45, no. 6, pp. 355–361, 2006. View at Publisher · View at Google Scholar
  12. F. J. T. Staal, M. Roederer, L. A. Herzenberg, and L. A. Herzenberg, “Intracellular thiols regulate activation of nuclear factor κB and transcription of human immunodeficiency virus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 24, pp. 9943–9947, 1990. View at Publisher · View at Google Scholar
  13. R. Schreck, P. Rieber, and P. A. Baeuerle, “Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV-1,” The EMBO Journal, vol. 10, no. 8, pp. 2247–2258, 1991. View at Google Scholar
  14. R. Schreck, K. Albermann, and P. A. Baeuerle, “Nuclear factor κB: an oxidative stress-responsive transcription factor of eukaryotic cells (a review),” Free Radical Research Communications, vol. 17, no. 4, pp. 221–237, 1992. View at Publisher · View at Google Scholar
  15. M. Meyer, R. Schreck, and P. A. Baeuerle, “H2O2 and antioxidants have opposite effects on activation of NF-κB and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor,” The EMBO Journal, vol. 12, no. 5, pp. 2005–2015, 1993. View at Google Scholar
  16. V. Nilakantan, B. T. Spear, and H. P. Glauert, “Liver-specific catalase expression in transgenic mice inhibits NF-κB activation and DNA synthesis induced by the peroxisome proliferator ciprofibrate,” Carcinogenesis, vol. 19, no. 4, pp. 631–637, 1998. View at Publisher · View at Google Scholar
  17. K. G. Calfee-Mason, B. T. Spear, and H. P. Glauert, “Effects of vitamin E on the NF-κB pathway in rats treated with the peroxisome proliferator, ciprofibrate,” Toxicology and Applied Pharmacology, vol. 199, no. 1, pp. 1–9, 2004. View at Publisher · View at Google Scholar
  18. Y. Li, H. P. Glauert, and B. T. Spear, “Activation of nuclear factor-κB by the peroxisome proliferator ciprofibrate in H4IIEC3 rat hepatoma cells and its inhibition by the antioxidants N-acetylcysteine and vitamin E,” Biochemical Pharmacology, vol. 59, no. 4, pp. 427–434, 2000. View at Publisher · View at Google Scholar
  19. K. N. Schmidt, P. Amstad, P. Cerutti, and P. A. Baeuerle, “The roles of hydrogen peroxide and superoxide as messengers in the activation of transcription factor NF-κB,” Chemistry & Biology, vol. 2, no. 1, pp. 13–22, 1995. View at Publisher · View at Google Scholar
  20. M. Hayakawa, H. Miyashita, I. Sakamoto et al., “Evidence that reactive oxygen species do not mediate NF-?B activation,” The EMBO Journal, vol. 22, no. 13, pp. 3356–3366, 2003. View at Publisher · View at Google Scholar
  21. M. J. FitzGerald, E. M. Webber, J. R. Donovan, and N. Fausto, “Rapid DNA binding by nuclear factor κB in hepatocytes at the start of liver regeneration,” Cell Growth & Differentiation, vol. 6, no. 4, pp. 417–427, 1995. View at Google Scholar
  22. A. A. Beg, W. C. Sha, R. T. Bronson, S. Ghosh, and D. Baltimore, “Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB,” Nature, vol. 376, no. 6536, pp. 167–170, 1995. View at Publisher · View at Google Scholar
  23. W. Vanden Berghe, L. Vermeulen, P. Delerive, K. De Bosscher, B. Staels, and G. Haegeman, “A paradigm for gene regulation: inflammation, NF-κB and PPAR,” Advances in Experimental Medicine and Biology, vol. 544, pp. 181–196, 2003. View at Google Scholar
  24. S. Maeda and M. Omata, “Inflammation and cancer: role of nuclear factor-kappaB activation,” Cancer Science, vol. 99, no. 5, pp. 836–842, 2008. View at Publisher · View at Google Scholar
  25. W. C. Sha, H.-C. Liou, E. I. Tuomanen, and D. Baltimore, “Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses,” Cell, vol. 80, no. 2, pp. 321–330, 1995. View at Publisher · View at Google Scholar
  26. A. A. Beg, W. C. Sha, R. T. Bronson, S. Ghosh, and D. Baltimore, “Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB,” Nature, vol. 376, no. 6536, pp. 167–170, 1995. View at Publisher · View at Google Scholar
  27. F. Kontgen, R. J. Grumont, A. Strasser et al., “Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression,” Genes & Development, vol. 9, no. 16, pp. 1965–1977, 1995. View at Publisher · View at Google Scholar
  28. G. Franzoso, L. Carlson, L. Poljak et al., “Mice deficient in nuclear factor (NF)-?B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture,” Journal of Experimental Medicine, vol. 187, no. 2, pp. 147–159, 1998. View at Publisher · View at Google Scholar
  29. F. Weih, D. Carrasco, S. K. Durham et al., “Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-?B/Rel family,” Cell, vol. 80, no. 2, pp. 331–340, 1995. View at Publisher · View at Google Scholar
  30. E. Pikarsky, R. M. Porat, I. Stein et al., “NF-?B functions as a tumour promoter in inflammation-associated cancer,” Nature, vol. 431, no. 7007, pp. 461–466, 2004. View at Publisher · View at Google Scholar
  31. T. Sakurai, S. Maeda, L. Chang, and M. Karin, “Loss of hepatic NF-κB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 28, pp. 10544–10551, 2006. View at Publisher · View at Google Scholar
  32. D. J. Van Antwerp, S. J. Martin, T. Kafri, D. R. Green, and I. M. Verma, “Suppression of TNF-α-induced apoptosis by NF-κB,” Science, vol. 274, no. 5288, pp. 787–789, 1996. View at Publisher · View at Google Scholar
  33. C.-Y. Wang, M. W. Mayo, and A. S. Baldwin Jr., “TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB,” Science, vol. 274, no. 5288, pp. 784–787, 1996. View at Publisher · View at Google Scholar
  34. A. A. Beg and D. Baltimore, “An essential role for NF-κB in preventing TNF-α-induced cell death,” Science, vol. 274, no. 5288, pp. 782–784, 1996. View at Publisher · View at Google Scholar
  35. M. H. Schoemaker, J. E. Ros, M. Homan et al., “Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes: NF-?B-regulated inhibitor of apoptosis protein 2 (cIAP2) prevents apoptosis,” Journal of Hepatology, vol. 36, no. 6, pp. 742–750, 2002. View at Publisher · View at Google Scholar
  36. Y. Xu, S. Bialik, B. E. Jones et al., “NF-?B inactivation converts a hepatocyte cell line TNF-a response from proliferation to apoptosis,” American Journal of Physiology, vol. 275, no. 4, part 1, pp. C1058–C1066, 1998. View at Google Scholar
  37. Z. Lu, E. Y. Lee, L. W. Robertson, H. P. Glauert, and B. T. Spear, “Effect of 2,2,4,4,5,5-hexachlorobiphenyl (PCB-153) on hepatocyte proliferation and apoptosis in mice deficient in the p50 subunit of the transcription factor NF-κB,” Toxicological Sciences, vol. 81, no. 1, pp. 35–42, 2004. View at Publisher · View at Google Scholar
  38. J. C. Tharappel, A. Nalca, A. B. Owens et al., “Cell proliferation and apoptosis are altered in mice deficient in the NF-?B p50 subunit after treatment with the peroxisome proliferator ciprofibrate,” Toxicological Sciences, vol. 75, no. 2, pp. 300–308, 2003. View at Publisher · View at Google Scholar
  39. R. A. DeAngelis, K. Kovalovich, D. E. Cressman, and R. Taub, “Normal liver regeneration in p50/nuclear factor κB1 knockout mice,” Hepatology, vol. 33, no. 4, pp. 915–924, 2001. View at Publisher · View at Google Scholar
  40. M. L. Chaisson, J. T. Brooling, W. Ladiges, S. Tsai, and N. Fausto, “Hepatocyte-specific inhibition of NF-κB leads to apoptosis after TNF treatment, but not after partial hepatectomy,” Journal of Clinical Investigation, vol. 110, no. 2, pp. 193–202, 2002. View at Publisher · View at Google Scholar
  41. A. Kato, M. J. Edwards, and A. B. Lentsch, “Gene deletion of NF-κB p50 does not alter the hepatic inflammatory response to ischemia/reperfusion,” Journal of Hepatology, vol. 37, no. 1, pp. 48–55, 2002. View at Publisher · View at Google Scholar
  42. B. H. Horwitz, P. Zelazowski, Y. Shen et al., “The p65 subunit of NF-?B is redundant with p50 during B cell proliferative responses, and is required for germline CH transcription and class switching to IgG3,” The Journal of Immunology, vol. 162, no. 4, pp. 1941–1946, 1999. View at Google Scholar
  43. C. M. Snapper, P. Zelazowski, F. R. Rosas et al., “B cells from p50/NF-?B knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching,” The Journal of Immunology, vol. 156, no. 1, pp. 183–191, 1996. View at Google Scholar
  44. C. M. Snapper, F. R. Rosas, P. Zelazowski et al., “B cells lacking RelB are defective in proliferative responses, but undergo normal B cell maturation to Ig secretion and Ig class switching,” Journal of Experimental Medicine, vol. 184, no. 4, pp. 1537–1541, 1996. View at Publisher · View at Google Scholar
  45. Y. Li, L. K. Leung, H. P. Glauert, and B. T. Spear, “Treatment of rats with the peroxisome proliferator ciprofibrate results in increased liver NF-κB activity,” Carcinogenesis, vol. 17, no. 11, pp. 2305–2309, 1996. View at Publisher · View at Google Scholar
  46. R. H. Costa, “HNF3 protein family,” in Liver Gene Expression, R. Tronche and M. Yaniv, Eds., pp. 183–205, R.G. Landes Company, New York, NY, USA, 1994. View at Google Scholar
  47. T. Ohmura, G. M. Ledda-Columbano, R. Piga et al., “Hepatocyte proliferation induced by a single dose of a peroxisome proliferator,” American Journal of Pathology, vol. 148, no. 3, pp. 815–824, 1996. View at Google Scholar
  48. M. Menegazzi, A. Carcereri-De Prati, H. Suzuki et al., “Liver cell proliferation induced by nafenopin and cyproterone acetate is not associated with increases in activation of transcription factors NF-?B and AP-1 or with expression of tumor necrosis factor a,” Hepatology, vol. 25, no. 3, pp. 585–592, 1997. View at Publisher · View at Google Scholar
  49. P. Espandiari, G. Ludewig, H. P. Glauert, and L. W. Robertson, “Activation of hepatic NF-κB by the herbicide Dicamba (2-methoxy-3,6-dichlorobenzoic acid) in female and male rats,” Journal of Biochemical and Molecular Toxicology, vol. 12, no. 6, pp. 339–344, 1998. View at Publisher · View at Google Scholar
  50. I. Rusyn, H. Tsukamoto, and R. G. Thurman, “WY-14 643 rapidly activates nuclear factor κB in Kupffer cells before hepatocytes,” Carcinogenesis, vol. 19, no. 7, pp. 1217–1222, 1998. View at Publisher · View at Google Scholar
  51. I. Rusyn, S. Yamashina, B. H. Segal et al., “Oxidants from nicotinamide adenine dinucleotide phosphate oxidase are involved in triggering cell proliferation in the liver due to peroxisome proliferators,” Cancer Research, vol. 60, no. 17, pp. 4798–4803, 2000. View at Google Scholar
  52. P. Delerive, P. Gervois, J.-C. Fruchart, and B. Staels, “Induction of IκBα expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-α activators,” The Journal of Biological Chemistry, vol. 275, no. 47, pp. 36703–36707, 2000. View at Publisher · View at Google Scholar
  53. J. C. Tharappel, M. L. Cunningham, B. T. Spear, and H. P. Glauert, “Differential activation of hepatic NF-κB in rats and hamsters by the peroxisome proliferators Wy-14,643, gemfibrozil, and dibutyl phthalate,” Toxicological Sciences, vol. 62, no. 1, pp. 20–27, 2001. View at Publisher · View at Google Scholar
  54. J. G. Fischer, H. P. Glauert, T. Yin, M. L. Sweeney-Reeves, N. Larmonier, and M. C. Black, “Moderate iron overload enhances lipid peroxidation in livers of rats, but does not affect NF-κB activation induced by the peroxisome proliferator, Wy-14,643,” The Journal of Nutrition, vol. 132, no. 9, pp. 2525–2531, 2002. View at Google Scholar
  55. A. A. Nanji, A. J. Dannenberg, K. Jokelainen, and N. M. Bass, “Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-α (PPARα)-regulated genes and is ameliorated by PPARα activation,” Journal of Pharmacology and Experimental Therapeutics, vol. 310, no. 1, pp. 417–424, 2004. View at Publisher · View at Google Scholar
  56. C. G. Woods, A. M. Burns, B. U. Bradford et al., “WY-14,643-induced cell proliferation and oxidative stress in mouse liver are independent of NADPH oxidase,” Toxicological Sciences, vol. 98, no. 2, pp. 366–374, 2007. View at Publisher · View at Google Scholar
  57. K. G. Calfee-Mason, E. Y. Lee, B. T. Spear, and H. P. Glauert, “Role of the p50 subunit of NF-κB in vitamin E-induced changes in mice treated with the peroxisome proliferator, ciprofibrate,” Food and Chemical Toxicology, vol. 46, no. 6, pp. 2062–2073, 2008. View at Publisher · View at Google Scholar
  58. Y. Li, H. P. Glauert, and B. T. Spear, “NFκB activity is increased by the peroxisome proliferator ciprofibrate in rats,” Proceedings of the American Association of Cancer Research, vol. 37, p. 160, 1996. View at Google Scholar
  59. S. Neschen, I. Moore, W. Regittnig et al., “Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content,” American Journal of Physiology, vol. 282, no. 2, pp. E395–E401, 2002. View at Google Scholar
  60. D. A. West, N. H. James, S. C. Cosulich et al., “Role for tumor necrosis factor a receptor 1 and interleukin-1 receptor in the suppression of mouse hepatocyte apoptosis by the peroxisome proliferator nafenopin,” Hepatology, vol. 30, no. 6, pp. 1417–1424, 1999. View at Publisher · View at Google Scholar
  61. R. Kleemann, L. Verschuren, B.-J. de Rooij et al., “Evidence for anti-inflammatory activity of statins and PPARa activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro,” Blood, vol. 103, no. 11, pp. 4188–4194, 2004. View at Publisher · View at Google Scholar
  62. S. C. Cosulich, N. H. James, M. R. C. Needham, P. P. Newham, K. R. Bundell, and R. A. Roberts, “A dominant megative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin,” Carcinogenesis, vol. 21, no. 9, pp. 1757–1760, 2000. View at Publisher · View at Google Scholar
  63. H. P. Glauert, A. Eyigor, J. C. Tharappel, S. Cooper, E. Y. Lee, and B. T. Spear, “Inhibition of hepatocarcinogenesis by the deletion of the p50 subunit of NF-κB in mice administered the peroxisome proliferator Wy-14,643,” Toxicological Sciences, vol. 90, no. 2, pp. 331–336, 2006. View at Publisher · View at Google Scholar
  64. I. Inoue, F. Itoh, S. Aoyagi et al., “Fibrate and statin synergistically increase the transcriptional activities of PPARa/RXRa and decrease the transactivation of NF?B,” Biochemical and Biophysical Research Communications, vol. 290, no. 1, pp. 131–139, 2002. View at Publisher · View at Google Scholar
  65. P. Delerive, K. De Bosscher, S. Besnard et al., “Peroxisome proliferator-activated receptor a negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-?B and AP-1,” The Journal of Biological Chemistry, vol. 274, no. 45, pp. 32048–32054, 1999. View at Publisher · View at Google Scholar
  66. N. Marx, G. K. Sukhova, T. Collins, P. Libby, and J. Plutzky, “PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells,” Circulation, vol. 99, no. 24, pp. 3125–3131, 1999. View at Google Scholar
  67. B. Staels, W. Koenig, A. Habib et al., “Activation of human aortic smooth-muscle cells is inhibited by PPARa but not by PPAR? activators,” Nature, vol. 393, no. 6687, pp. 790–793, 1998. View at Publisher · View at Google Scholar
  68. M. E. Poynter and R. A. Daynes, “Peroxisome proliferator-activated receptor α activation modulates cellular redox status, represses nuclear factor-κB signaling, and reduces inflammatory cytokine production in aging,” The Journal of Biological Chemistry, vol. 273, no. 49, pp. 32833–32841, 1998. View at Publisher · View at Google Scholar
  69. F. T. Wunderlich, T. Luedde, S. Singer et al., “Hepatic NF-?B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 4, pp. 1297–1302, 2008. View at Publisher · View at Google Scholar
  70. Y. Li, J. C. Tharappel, S. Cooper, M. Glenn, H. P. Glauert, and B. T. Spear, “Expression of the hydrogen peroxide-generating enzyme fatty acyl CoA oxidase activates NF-κB,” DNA and Cell Biology, vol. 19, no. 2, pp. 113–120, 2000. View at Publisher · View at Google Scholar
  71. B. G. Lake, J. G. Evans, M. E. Cunninghame, and R. J. Price, “Comparison of the hepatic effects of nafenopin and WY-14,643 on peroxisome proliferation and cell replication in the rat and Syrian hamster,” Environmental Health Perspectives, vol. 101, supplement 5, pp. 241–247, 1993. View at Google Scholar
  72. J. M. Durnford, M. R. Hejtmancik, P. J. Kurtz et al., “Peroxisomal enzyme activity and cell proliferation in rats, mice and hamsters exposed for 13-weeks to Wy-14,643 and gemfibrozil,” Toxicological Sciences, vol. 42, supplement 1, p. 11, 1998. View at Google Scholar
  73. M. L. O'Brien, M. L. Cunningham, B. T. Spear, and H. P. Glauert, “Effects of peroxisome proliferators on glutathione and glutathione-related enzymes in rats and hamsters,” Toxicology and Applied Pharmacology, vol. 171, no. 1, pp. 27–37, 2001. View at Publisher · View at Google Scholar
  74. M. L. O'Brien, T. P. Twaroski, M. L. Cunningham, H. P. Glauert, and B. T. Spear, “Effects of peroxisome proliferators on antioxidant enzymes and antioxidant vitamins in rats and hamsters,” Toxicological Sciences, vol. 60, no. 2, pp. 271–278, 2001. View at Publisher · View at Google Scholar