Cell Growth & Differentiation, Vol 9, Issue 9 815-825, Copyright © 1998 by American Association of Cancer Research

ARTICLES

Regulation of apoptosis in mouse hepatocytes and alteration of apoptosis by nongenotoxic carcinogens

JG Christensen, AJ Gonzales, RC Cattley and TL Goldsworthy
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709-2137, USA. christensen@CIIT.org

Regulation of apoptosis is an important component of multistage hepatocarcinogenesis. The objectives of the present study were to characterize apoptosis regulation in primary mouse hepatocytes and to determine whether nongenotoxic carcinogens alter apoptosis regulation. Bleomycin-induced apoptosis was accompanied by decreases in bcl-2 and bcl-xl and increases in p53, bak, and bax protein levels. Transforming growth factor (TGF)-beta-induced apoptosis was accompanied by decreased bcl-xL and increased bak. Bleomycin-induced apoptosis was partially dependent on p53, whereas TGF-beta-induced apoptosis was independent of p53. Phenobarbital inhibited both TGF-beta and bleomycin-induced apoptosis and the normal regulation of p53, bcl-2, and bax. Nafenopin inhibited apoptosis through a mechanism dependent on PPAR-alpha and inhibited the normal regulation of bcl-2 and bak. 2,3,7,8-Tetrachlorodibenzo-p-dioxin did not alter apoptosis or its regulation. Apoptosis was increased in hepatocytes from bcl-2-null mice, which indicated that the bcl-2 family contributes to hepatocyte apoptosis regulation. This study demonstrated that apoptosis regulation in mouse hepatocytes involves distinct pathways and that diverse nongenotoxic carcinogens differentially alter molecular pathways that represent targets for hepatocarcinogenesis.

This article has been cited by other articles:

				M. Iida, C. H. Anna, N. D. Gaskin, N. J. Walker, and T. R. Devereux The Putative Tumor Suppressor Tsc-22 is Downregulated Early in Chemically Induced Hepatocarcinogenesis and may be a Suppressor of Gadd45b Toxicol. Sci., September 1, 2007; 99(1): 43 - 50. [Abstract] [Full Text] [PDF]

				M. Iida, C. H. Anna, W. M. Holliday, J. B. Collins, M. L. Cunningham, R. C. Sills, and T. R. Devereux Unique patterns of gene expression changes in liver after treatment of mice for 2 weeks with different known carcinogens and non-carcinogens Carcinogenesis, March 1, 2005; 26(3): 689 - 699. [Abstract] [Full Text] [PDF]

				K.-T. Park, K. A. Mitchell, G. Huang, and C. J. Elferink The Aryl Hydrocarbon Receptor Predisposes Hepatocytes to Fas-Mediated Apoptosis Mol. Pharmacol., March 1, 2005; 67(3): 612 - 622. [Abstract] [Full Text] [PDF]

				J. Chen, M. Delannoy, S. Odwin, P. He, M. A. Trush, and J. D. Yager Enhanced Mitochondrial Gene Transcript, ATP, Bcl-2 Protein Levels, and Altered Glutathione Distribution in Ethinyl Estradiol-Treated Cultured Female Rat Hepatocytes Toxicol. Sci., October 1, 2003; 75(2): 271 - 278. [Abstract] [Full Text] [PDF]

				M. Iida, C. H. Anna, J. Hartis, M. Bruno, B. Wetmore, J. R. Dubin, S. Sieber, L. Bennett, M. L. Cunningham, R. S. Paules, et al. Changes in global gene and protein expression during early mouse liver carcinogenesis induced by non-genotoxic model carcinogens oxazepam and Wyeth-14,643 Carcinogenesis, April 1, 2003; 24(4): 757 - 770. [Abstract] [Full Text] [PDF]

				R. A. Roberts Evidence for Cross Talk between PPAR{alpha} and p38 MAP Kinase Toxicol. Sci., August 1, 2002; 68(2): 270 - 274. [Full Text] [PDF]

				B.-C. Kim, M. Mamura, K. S. Choi, B. Calabretta, and S.-J. Kim Transforming Growth Factor {beta}1 Induces Apoptosis through Cleavage of BAD in a Smad3-Dependent Mechanism in FaO Hepatoma Cells Mol. Cell. Biol., March 1, 2002; 22(5): 1369 - 1378. [Abstract] [Full Text] [PDF]

				C. L. Buenemann, C. Willy, A. Buchmann, A. Schmiechen, and M. Schwarz Transforming growth factor-{beta}1-induced Smad signaling, cell-cycle arrest and apoptosis in hepatoma cells Carcinogenesis, March 1, 2001; 22(3): 447 - 452. [Abstract] [Full Text] [PDF]

				B. HERRERA, ALBERTO. M. ALVAREZ, A. SANCHEZ, M. FERNANDEZ, C. RONCERO, M. BENITO, and I. FABREGAT Reactive oxygen species (ROS) mediates the mitochondrial-dependent apoptosis induced by transforming growth factor {beta} in fetal hepatocytes FASEB J, March 1, 2001; 15(3): 741 - 751. [Abstract] [Full Text] [PDF]

				S. C. Hasmall, D. A. West, K. Olsen, and R. A. Roberts Role of hepatic non-parenchymal cells in the response of rat hepatocytes to the peroxisome proliferator nafenopin in vitro Carcinogenesis, December 1, 2000; 21(12): 2159 - 2165. [Abstract] [Full Text] [PDF]

				A B DeAngelo Response to "Epigenetic mechanisms of chemical carcinogenesis" by James E. Klaunig, Lisa M. Kamendulis, and Xu Yong Human and Experimental Toxicology, October 1, 2000; 19(10): 561 - 562. [PDF]

				J. Chen, M. Gokhale, B. Schofield, S. Odwin, and J. D. Yager Inhibition of TGF-{beta}-induced apoptosis by ethinyl estradiol in cultured, precision cut rat liver slices and hepatocytes Carcinogenesis, June 1, 2000; 21(6): 1205 - 1211. [Abstract] [Full Text] [PDF]

				S. Cosulich, N. James, and R. Roberts Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators Carcinogenesis, April 1, 2000; 21(4): 579 - 584. [Abstract] [Full Text] [PDF]

				E. I. Salim, H. Wanibuchi, K. Morimura, S. Kim, Y. Yano, S. Yamamoto, and S. Fukushima Inhibitory effects of 1,3-diaminopropane, an ornithine decarboxylase inhibitor, on rat two-stage urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine Carcinogenesis, February 1, 2000; 21(2): 195 - 203. [Abstract] [Full Text] [PDF]

				R. A. Roberts and I. Kimber Cytokines in non-genotoxic hepatocarcinogenesis Carcinogenesis, August 1, 1999; 20(8): 1397 - 1402. [Full Text] [PDF]

				J. G. Christensen, E. H. Romach, L. N. Healy, A. J. Gonzales, S. P. Anderson, D. E. Malarkey, J. C. Corton, T. R. Fox, R. C. Cattley, and T. L. Goldsworthy Altered bcl-2 family expression during non-genotoxic hepatocarcinogenesis in mice Carcinogenesis, August 1, 1999; 20(8): 1583 - 1590. [Abstract] [Full Text] [PDF]