[Relationship between the Akt-regulated direct p53 mitochondrial translocation and the resistance to cisplatin of ovarian cancer cells].

ABSTRACT

OBJECTIVE: To explore Akt-regulated direct p53 mitochondrial translocation in cisplatin-induced apoptosis in ovarian cancer cells and the relationship between this and chemoresistance in ovarian cancer. METHODS: Chemosensitive ovarian cancer cell lines (OV2008 and A2780s) and chemoresistant cells (C13(*) and A2780cp) were treated with cisplatin and whole cell and mitochondrial p53 contents were determined by Western blot. The p53 accumulation in mitochondria was determined in purified mitochondrial fractions in cisplatin-sensitive and -resistant ovarian cancer cells. Akt1/2 siRNA were transfected into C13(*) cells. Cisplatin-induced apoptosis was measured by Hoechst staining and p53 translocation was determined by Western blot. RESULTS: Cisplatin induced mitochondrial p53 accumulation and apoptosis in chemosensitive cells (P < 0.05), but not in resistant cells (P > 0.05). Over-expression of active Akt2 inhibited p53 directly translocate to mitochondria, and downregulation of Akt by Akt1/2 siRNA increased p53 mitochondrial accumulation and sensitize C13(*) cells to cisplatin treatment. CONCLUSIONS: Cisplatin induces direct p53 mitochondrial accumulation in chemosensitive cells, and Akt confers resistance in ovarian cancer cells, in part, by regulating the direct action of p53 in mitochondrial death pathway.