Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells

Cisplatin-centered chemotherapy is a key treatment for ovarian cancer, but resistance to chemotherapeutic agents remains a major cause of treatment fa ilure. Multiple factors are known to contribute to the development of this chemoresistance, Although it has been demonstrated that X-linked inhibitor of apoptosis protein (Xiap) prevents apoptosis by inhibiting effector caspa ses, if and how it is important in chemoresistance in ovarian cancer has no t been studied. The effects of Xiap down-regulation and/or restoration of w ild type p53 by recombinant adenovirus infection were examined on four ovar ian epithelial cancer cell lines [C13*, A2780-s (wild type p53), A2780-cp ( mutant p53), and SKOV3 (null p53)], Apoptosis and protein expression (e.g., Xiap, caspase-3, p53, MDM2, and p21(waf1)) were assessed by Hoechst 33258 stain and Western blot, respectively, We demonstrated that Xiap down-regula tion following adenoviral antisense expression induces apoptosis in the wil d-type p53 cells, but not in the mutated or null cells, Xiap down-regulatio n resulted in caspase-3 activation, caspase-mediated MDM2 processing, and p 53 accumulation. Restoration of wild type p53 in the p53-mutated or -null c ells significantly enhanced the proapoptotic effect of Xiap antisense expre ssion. Downregulation of Xiap induced apoptosis in chemoresistant ovarian c ancer cells, a process dependent on p53 status.