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J. Biol. Chem., Vol. 279, Issue 21, 22747-22758, May 21, 2004

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Arsenite Sensitizes Human Melanomas to Apoptosis via Tumor Necrosis Factor -mediated Pathway^*

Vladimir N. Ivanov and Tom K. Hei¶

From the Center for Radiological Research, College of Physicians and Surgeons and the ^¶Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032

Arsenic is a well established human carcinogen and is associated with a variety of cancers including those of the skin. Paradoxically, arsenic has also been used, amid at low doses, in the treatment of leukemia for over a century. Here we demonstrate that low to moderate concentrations of arsenite (2-10 µM) that has little or no effect on normal melanocytes may induce apoptosis of human melanomas including highly metastatic ones despite their low surface Fas levels. The two prerequisites that dictate apoptotic response of melanomas upon arsenite treatment are low nuclear NF-B activity and an endogenous expression of tumor necrosis factor . Under these conditions, melanoma cells acquired sensitivity to tumor necrosis factor -mediated killing. On the other hand, signaling pathways including those of phosphatidylinositol 3-kinase-AKT, MEK-ERK, and JNK play a protective role against arsenite-induced oxidative stress and apoptosis in melanoma cells. Suppression of these pathways dramatically accelerates arsenite-induced apoptosis. Taken together, these data could provide potential approaches to sensitize melanomas to the cytotoxic effects of arsenite through modulating the signaling pathways.

Received for publication, December 23, 2003 , and in revised form, March 15, 2004.

^* This work was supported by National Institutes of Health Grant ES 11804, Superfund Grant P42 ES 10349, and Environmental Center Grant P30 ES 09089. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Center for Radiological Research, Columbia University, VC11-204, 630 W. 168th St., New York, NY 10032. Tel.: 212-305-0846; Fax: 212-305-3229; E-mail: vni3{at}columbia.edu.

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