title: Inhibition of benzopyrene-diol-epoxide (BPDE)-induced bax and caspase-9 by cadmium: role of mitogen activated protein kinase.
abstract: Cadmium, a major metal constituent of tobacco smoke, elicits synergistic enhancement of cell transformation when combined with benzo[a]pyrene (BP) or other polynuclear aromatic hydrocarbons (PAHs). The mechanism underlying this synergism is not clearly understood. Present study demonstrates that (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), an ultimate carcinogen of BP, induces apoptosis in human leukemic HL-60 cells and others, and cadmium at non-cytotoxic concentration inhibits BPDE-induced apoptosis. We observed that BPDE treatment also activates all three MAP kinases e.g. ERK1/2, p38 and JNK in HL-60 cells, and inhibition of BPDE-induced apoptosis by cadmium is associated with down-regulation of pro-apoptotic bax induction/caspase-9 activation and up-regulation of ERK phosphorylation, whereas p38 MAP kinase and c-Jun phosphorylation (indicative of JNK activation) remain unaffected. Inhibition of ERKs by prior treatment of cells with 10muM U0126 relieves cadmium-mediated inhibition of apoptosis/bax induction/caspase-9 activation. Our results suggest that cadmium inhibits BPDE-induced apoptosis by modulating apoptotic signaling through up-regulation of ERK, which is known to promote cell survival.
authors.affiliation: State University of New York College at Buffalo, Environ. Toxicol. & Chem., Great Lakes Center, 1300 Elmwood Avenue, Buffalo, NY 14222, United States.
authors.forename: Jagat J
authors.initials: JJ
authors.lastname: Mukherjee
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Harish
authors.initials: H
authors.lastname: Sikka
authors.forename: Subodh
authors.initials: S
authors.lastname: Kumar
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002104:Cadmium / Q000633:toxicity*; D053453:Caspase 9 / Q000096:biosynthesis*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D004785:Environmental Pollutants / Q000633:toxicity; D004790:Enzyme Induction / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*
chemical_list: C494826:BAX protein, human; D002070:Butadienes; D004785:Environmental Pollutants; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D012906:Smoke; C113580:U 0126; D051028:bcl-2-Associated X Protein; D002104:Cadmium; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C506433:CASP9 protein, human; D053453:Caspase 9