2,2 ',4,6,6 '-pentachlorobiphenyl-induced apoptosis is limited by cyclooxygenase-2 induction
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- 2,2 ',4,6,6 '-pentachlorobiphenyl-induced apoptosis is limited by cyclooxygenase-2 induction
- Kim, SH; Kim, YH; Shin, KJ; Oh, YS; Lee, CS; Kang, KO; Ryu, SH; Suh, Pann-Ghill
- Compensation; Cyclooxygenase-2; Polychlorinated biphenyl
- Issue Date
- OXFORD UNIV PRESS
- TOXICOLOGICAL SCIENCES, v.83, no.2, pp.397 - 404
- Polychlorinated biphenyls (PCBs), a group of persistent and wide-spread 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 Be 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 toxicy.
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