title: 2,2',4,6,6'-Pentachlorobiphenyl-induced apoptosis is limited by cyclooxygenase-2 induction.
abstract: Polychlorinated biphenyls (PCBs), a group of persistent and widespread environmental pollutants, are considered to be immunotoxic, carcinogenic, and to induce apoptosis. However, the cellular mechanisms underlying the action of PCBs have not been established. Here, we investigated the effects of PCBs on the induction of cyclooxygenase-2 (COX-2). Among the several congeners examined, only 2,2',4,6,6'-pentachlorobiphenyl (PeCB) specifically increased the COX-2 promoter activity, and the levels of COX-2 mRNA and protein, and thereby enhanced prostaglandin E2 (PGE2) synthesis in Rat-1 cells. By conducting mutation analyses of the COX-2 promoter and its transcription factor, we found that the CRE site in COX-2 promoter and c-Jun are important for increased COX-2 promoter activity induced by 2,2',4,6,6'-PeCB. In addition, 2,2',4,6,6'-PeCB-stimulated COX-2 induction was reduced by the specific MAPK kinase (MEK) inhibitor, PD98059, and in p53-deficient cells, implying that COX-2 induction requires the activation of ERK1/2 MAPK and p53. The selective COX-2 inhibitor, NS-398, potentiated the 2,2',4,6,6'-PeCB-induced mitochondrial apoptotic pathway involved in Bcl-xL attenuation, cytochrome c release and the subsequent activation of caspase-3. Furthermore, the cell death was prevented by PGE2 treatment, suggesting that 2,2',4,6,6'-PeCB-induced apoptosis is restricted by prostaglandin upregulation by COX-2. Taken together, these results demonstrate that 2,2',4,6,6'-PeCB-induced COX-2 expression may be an important compensatory mechanism for abating 2,2',4,6,6'-PeCB toxicity.
authors.affiliation: Department of Life Science, Division of Molecular and Life Science, and School of Environmental Science and Engineering, Pohang University of Science and Technology, Pohang 790-784, Kyungbuk, Republic of Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Kim
authors.forename: Kum-Joo
authors.initials: KJ
authors.lastname: Shin
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Oh
authors.forename: Chang Sup
authors.initials: CS
authors.lastname: Lee
authors.forename: Kyung-Ok
authors.initials: KO
authors.lastname: Kang
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004252:DNA Mutational Analysis; D015232:Dinoprostone / Q000096:biosynthesis / Q000235:genetics; D004785:Environmental Pollutants / Q000633:toxicity*; D004790:Enzyme Induction; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051379:Mice; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020218:Response Elements / Q000187:drug effects; D014162:Transfection
chemical_list: D004785:Environmental Pollutants; D012333:RNA, Messenger; D011078:Polychlorinated Biphenyls; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C417207:2,2',4,6,6'-pentachlorobiphenyl