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


OBJECTIVE
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.
Ouyang
Weiming
W
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA.
Zhang
Dongyun
D
Ma
Qian
Q
Li
Jingxia
J
Huang
Chuanshu
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004785:Environmental Pollutants / Q000633:toxicity*; D000078404:Epidermal Cells; D051550:I-kappa B Kinase / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced
D018053:Arsenites; D004785:Environmental Pollutants; D016328:NF-kappa B; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C015001:arsenite