title: Cyclooxygenase-2 (COX-2) mediates arsenite inhibition of UVB-induced cellular apoptosis in mouse epidermal Cl41 cells.
abstract: Inorganic arsenic is an environmental human carcinogen, and has been shown to act as a co-carcinogen with solar ultraviolet (UV) radiation in mouse skin tumor induction even at low concentrations. However, the precise mechanism of its co-carcinogenic action is largely unknown. Apoptosis plays an essential role as a protective mechanism against neoplastic development in the organism by eliminating genetically damaged cells. Thus, suppression of apoptosis is thought to contribute to carcinogenesis. It is known that cyclooxygenase-2 (COX-2) can promote carcinogenesis by inhibiting cell apoptosis under stress conditions; and our current studies investigated the potential contribution of COX-2 to the inhibitory effect of arsenite in UV-induced cell apoptosis in mouse epidermal Cl41 cells. We found that treatment of cells with low concentration (5 μM) arsenite attenuated cellular apoptosis upon UVB radiation accompanied with a coinductive effect on COX-2 expression and nuclear factor-κB (NFκB) transactivation. Our results also showed that the COX-2 induction by arsenite and UVB depended on an NFκB pathway because COX-2 co-induction could be attenuated in either p65-deficient or p50-deficient cells. Moreover, UVB-induced cell apoptosis could be dramatically reduced by the introduction of exogenous COX-2 expression, whereas the inhibitory effect of arsenite on UVB-induced cell apoptosis could be impaired in COX-2 knockdown C141 cells. Our results indicated that COX-2 mediated the anti-apoptotic effect of arsenite in UVB radiation through an NFκB-dependent pathway. Given the importance of apoptosis evasion during carcinogenesis, we anticipated that COX-2 induction might be at least partially responsible for the co-carcinogenic effect of arsenite on UVB-induced skin carcinogenesis.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, 10987, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zuo
authors.forename: W
authors.initials: W
authors.lastname: Ouyang
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Costa
authors.forename: C
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D018053:Arsenites / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004817:Epidermis / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects*; D017930:Genes, Reporter; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D034622:RNA Interference; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: D018053:Arsenites; D002274:Carcinogens, Environmental; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D018808:Transcription Factor AP-1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C015001:arsenite