Cyclooxygenase-2 induction by arsenite through the IKKbeta/NFkappaB pathway exerts an antiapoptotic effect in mouse epidermal Cl41 cells.

Content Provider	Europe PMC
Author	Ouyang, Weiming Zhang, Dongyun Ma, Qian Li, Jingxia Huang, Chuanshu
Copyright Year	2007
Abstract	BackgroundArsenic 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.ObjectivesIn 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.MethodsWe 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.ResultsThe induction of COX-2 by arsenite was inhibited in Cl41 cells transfected with IKKβ-KM, a dominant mutant inhibitor of kβ (Ikβ) kinase (IKKβ), and in IKKβ-knockout (IKKβ−/−) mouse embryonic fibroblasts (MEFs). IKKβ/nuclear factor κB (NFκB) 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 IKKβ-KM or COX-2 small interference RNA (siCOX-2). In addition, IKKβ−/− MEFs stably transfected with COX-2 showed more resistance to arsenite-induced apoptosis compared with the same control vector–transfected cells.ConclusionsThese results demonstrate that arsenite exposure can induce COX-2 expression through the IKKβ/NFκB 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.
ISSN	00916765
Journal	Environmental Health Perspectives
Volume Number	115
PubMed Central reference number	PMC1852668
Issue Number	4
PubMed reference number	17450217
e-ISSN	15529924
DOI	10.1289/ehp.9588
Language	English
Publisher	National Institute of Environmental Health Sciences
Publisher Date	2006-12-14
Access Restriction	Open
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Subject Keyword	apoptosis arsenite carcinogenesis COX-2 NFκB
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Public Health, Environmental and Occupational Health