title: Catalase protects HepG2 cells from apoptosis induced by DNA-damaging agents by accelerating the degradation of p53.
abstract: Oxidants such as H(2)O(2) play a role in the toxicity of certain DNA-damaging agents, a process that often involves the tumor suppressor p53. H(2)O(2) is rapidly degraded by catalase, which protects cells against oxidant injury. To study the effect of catalase on apoptosis induced by DNA-damaging agents, HepG2 cells were infected with adenovirus containing the cDNA of catalase (Ad-Cat). Forty-eight hours after infection, catalase protein and activity was increased 7-10-fold compared with control cells infected with Ad-LacZ. After treatment with Vp16 or mitomycin C, control cells underwent apoptosis in a p53-dependent manner; however, overexpression of catalase inhibited this apoptosis. Basal levels as well as Vp16- or mitomycin C-stimulated levels of p53 and p21 protein were decreased in the catalase-overexpressing cells as compared with control cells; however, p53 mRNA levels were not decreased by catalase. There was no difference in p53 protein synthesis between catalase-overexpressing cells and control cells. However, pulse-chase experiments indicated that p53 protein degradation was enhanced in the catalase-overexpressing cells. Proteasome inhibitors but not calpeptin prevented the catalase-mediated decrease of p53 content. Whereas Vp16 increased, catalase overexpression decreased the phosphorylation of p53. The protein phosphatase inhibitor okadaic acid did not prevent the catalase-mediated down-regulation of p53 or phosphorylated p53. These results demonstrate that catalase protects HepG2 cells from apoptosis induced by DNA-damaging agents in association with decreasing p53 phosphorylation; the latter may lead to an acceleration in the degradation of p53 protein by the proteasome complex. This suggests that the level of catalase may play a critical role in cell-induced resistance to the effects of anti-cancer drugs which up-regulate p53.
authors.affiliation: Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Jingxiang
authors.initials: J
authors.lastname: Bai
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Cederbaum
mesh_terms: D000256:Adenoviridae; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002374:Catalase / Q000235:genetics*; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D016158:Genes, p53; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress / Q000235:genetics*; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D019384:Nucleic Acid Synthesis Inhibitors; D016685:Mitomycin; D005047:Etoposide; D002374:Catalase