Cisplatin-induced nitrosylation of p53 prevents its mitochondrial translocation

Abstract

The cellular response to DNA damage has been reported to involve rapid transcription-independent translocation of p53 to mitochondria. We show here that the DNA-damaging cisplatin-derived anticancer agent oxaliplatin induced both mitochondrial translocation and subsequent Bcl-xL interaction, whereas cisplatin did neither. The differential response was due to nitrosative modification of p53. Thus, cisplatin, but not oxaliplatin, induced increased expression of inducible nitric oxide synthase (iNOS). Cisplatin treatment in the presence of an iNOS inhibitor (1400W) allowed p53 mitochondrial translocation. Conversely, oxaliplatin-induced translocation of p53 was prevented by cotreatment with an exogenous NO donor. In cisplatin-treated cells, nuclear but not mitochondrial p53 showed nitrotyrosinylation that was inhibitable by 1400W. We conclude that nitrosative protein modification is more prominent in the response to cisplatin than oxaliplatin and that nitrosative modification of p53 is a major determinant of p53 subcellular location.