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J. Biol. Chem., Vol. 279, Issue 1, 288-298, January 2, 2004

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Depletion of Endogenous Nitric Oxide Enhances Cisplatin-induced Apoptosis in a p53-dependent Manner in Melanoma Cell Lines^*

Chi-Hui Tang and Elizabeth A. Grimm

From the University of Texas Graduate School of Biomedical Sciences and the Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The expression of inducible nitric-oxide synthase in melanoma tumor cells was recently shown to correlate strongly with poor patient survival after combination biochemotherapy (p < 0.001). Furthermore, evidence suggests that nitric oxide, a reaction product of nitricoxide synthase, exhibits antiapoptotic activity in melanoma cells. We therefore hypothesized that nitric oxide antagonizes chemotherapy-induced apoptosis. Whether nitric oxide is capable of regulating cell growth and apoptotic responses to cisplatin treatment in melanoma cell lines was evaluated. We demonstrate herein that depletion of endogenously produced nitric oxide can inhibit melanoma proliferation and promote apoptosis. Moreover, our data indicate that the depletion of nitric oxide leads to changes in cell cycle regulation and enhances cisplatin-induced apoptosis in melanoma cells. Strikingly, we observed that the depletion of nitric oxide inhibits cisplatin-induced wild type p53 accumulation and p21^{Waf1/Cip1/Sdi1} expression in melanoma cells. When cisplatin-induced p53 binding to the p21^{Waf1/Cip1/Sdi1} promoter was examined, it was found that nitric oxide depletion significantly reduced the presence of p53-DNA complexes after cisplatin treatment. Furthermore, dominant negative inhibition of p53 activity enhanced cisplatin-induced apoptosis. Together, these data strongly suggest that endogenously produced nitric oxide is required for cisplatin-induced p53 activation and p21^{Waf1/Cip1/Sdi1} expression, which can regulate melanoma sensitivity to cisplatin.

Received for publication, October 1, 2003 , and in revised form, October 22, 2003.

^* This work was supported in part by the National Institutes of Health Grant R01 CA90282 (to E. A. G.), a Rosalie B. Hite Research Fellowship (to C.-H. T.), Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center and Health Science Center, Houston, and The University of Texas Graduate School of Biomedical Sciences, Houston. 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.

Partial fulfillment of the requirements for a Ph.D. degree.

To whom correspondence should be addressed. Tel.: 713-792-3667; Fax: 713-792-2070; E-mail: egrimm{at}mdanderson.org.

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