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.
Keywords: Apoptosis, arsenite, COX-2, NF-κB, UVB, activator protein-1, B-cell lymphoma-2, B-cell lymphoma-extra large, bronchial epithelial cell line, Dulbecco's Modified Eagle’s Medium, fetal bovine serum, heme oxygenase 1, mouse embryonic fibroblasts, minimal essential medium
Current Cancer Drug Targets
Title:Cyclooxygenase-2 (COX-2) Mediates Arsenite Inhibition of UVB-Induced Cellular Apoptosis in Mouse Epidermal Cl41 Cells
Volume: 12 Issue: 6
Author(s): Z. Zuo, W. Ouyang, J. Li, M. Costa and C. Huang
Affiliation:
Keywords: Apoptosis, arsenite, COX-2, NF-κB, UVB, activator protein-1, B-cell lymphoma-2, B-cell lymphoma-extra large, bronchial epithelial cell line, Dulbecco's Modified Eagle’s Medium, fetal bovine serum, heme oxygenase 1, mouse embryonic fibroblasts, minimal essential medium
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.
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Zuo Z., Ouyang W., Li J., Costa M. and Huang C., Cyclooxygenase-2 (COX-2) Mediates Arsenite Inhibition of UVB-Induced Cellular Apoptosis in Mouse Epidermal Cl41 Cells, Current Cancer Drug Targets 2012; 12 (6) . https://dx.doi.org/10.2174/156800912801784802
DOI https://dx.doi.org/10.2174/156800912801784802 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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