Cyclooxygenase-2 induction by arsenite through the IKKbeta/NFkappaB pathway exerts an antiapoptotic effect in mouse epidermal Cl41 cells.
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Ouyang W, Zhang D, Ma Q, Li J, Huang C
Cyclooxygenase-2 induction by arsenite through the IKKbeta/NFkappaB pathway exerts an antiapoptotic effect in mouse epidermal Cl41 cells.
Environ Health Perspect. 2007 Apr;115(4):513-8. Epub 2006 Dec 14.
- PubMed ID
- 17450217 [ View in PubMed]
- Abstract
BACKGROUND: Arsenic contamination has become a major public health concern worldwide. Epidemiologic data show that long-term arsenic exposure results in the risk of skin cancer. However, the mechanisms underlying carcinogenic effects of arsenite on skin remain to be studied. OBJECTIVES: In the present study we evaluated cyclooxygenase-2 (COX-2) expression, the signaling pathways leading to COX-2 induction, and its antiapoptotic function in the response to arsenite exposure in mouse epidermal JB6 Cl41 cells. METHODS: We used the luciferase reporter assay and Western blots to determine COX-2 induction by arsenite. We utilized dominant negative mutant, genetic knockout, gene knockdown, and gene overexpression approaches to elucidate the signaling pathway involved in COX-2 induction and its protective effect on cell apoptosis. RESULTS: The induction of COX-2 by arsenite was inhibited in Cl41 cells transfected with IKKbeta-KM, a dominant mutant inhibitor of kbeta (Ikbeta) kinase (IKKbeta), and in IKKbeta-knockout (IKKbeta(-/-)) mouse embryonic fibroblasts (MEFs). IKKbeta/nuclear factor kappaB (NFkappaB) pathway-mediated COX-2 induction exerted an antiapoptotic effect on the cells exposed to arsenite because cell apoptosis was significantly enhanced in the Cl41 cells transfected with IKKbeta-KM or COX-2 small interference RNA (siCOX-2). In addition, IKKbeta(-/-) MEFs stably transfected with COX-2 showed more resistance to arsenite-induced apoptosis compared with the same control vector-transfected cells. CONCLUSIONS: These results demonstrate that arsenite exposure can induce COX-2 expression through the IKKbeta/NFkappaB pathway, which thereby exerts an antiapoptotic effect in response to arsenite. In light of the importance of apoptosis evasion during carcinogenesis, we anticipate that COX-2 induction may be at least partially responsible for the carcinogenic effect of arsenite on skin.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Arsenic trioxide Inhibitor of nuclear factor kappa-B kinase subunit beta Protein Humans YesInducerDetails