TY - JOUR
T1 - Depletion of Endogenous Nitric Oxide Enhances Cisplatin-induced Apoptosis in a p53-dependent Manner in Melanoma Cell Lines
AU - Tang, Chi Hui
AU - Grimm, Elizabeth A.
PY - 2004/1/2
Y1 - 2004/1/2
N2 - 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 nitric-oxide 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 p21Waf1/Cip1/Sdi1 expression in melanoma cells. When cisplatin-induced p53 binding to the p21Waf1/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.
AB - 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 nitric-oxide 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 p21Waf1/Cip1/Sdi1 expression in melanoma cells. When cisplatin-induced p53 binding to the p21Waf1/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.
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U2 - 10.1074/jbc.M310821200
DO - 10.1074/jbc.M310821200
M3 - Article
C2 - 14576150
AN - SCOPUS:0345791531
SN - 0021-9258
VL - 279
SP - 288
EP - 298
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 1
ER -