Human ovarian cancer and cisplatin resistance: Possible role of inhibitor of apoptosis proteins

The inhibitor of apoptosis proteins (IAPs) constitutes a family of highly c onserved apoptosis suppressor proteins that were originally identified in b aculoviruses. Although IAP homologs have recently been demonstrated to supp ress apoptosis in mammalian cells, their expression and role in human ovari an epithelial cancer and chemotherapy resistance are unknown. In the presen t study we used cisplatin-sensitive and -resistant human ovarian surface ep ithelial (hOSE) cancer cell lines and adenoviral antisense and sense comple mentary DNA expression to examine the role of IAP in the regulation of apop tosis in human ovarian cancer cells and chemoresistance. Antisense down-reg ulation of X-linked inhibitor of apoptosis protein (Xiap), but not human in hibitor of apoptosis protein-2 (Hiap-2), induced apoptosis in cisplatin-sen sitive and, to a lesser extent, in -resistant cells. Cisplatin consistently decreased Xiap content and induced apoptosis in the cisplatin-sensitive, b ut not cisplatin-resistant, cells. Hiap-2 expression was either unaffected or inhibited to a lesser extent. The inhibition of IAP protein expression a nd induction of apoptosis by cisplatin was time and concentration dependent . Infection of cisplatin-sensitive cells with adenoviral sense Xiap complem entary DNA resulted in overexpression of Xiap and markedly attenuated the a bility of cisplatin to induce apoptosis. Immunohistochemical localization o f the LAPs in hOSE tumors demonstrated the presence of Xiap and Hiap-2, wit h their levels being highest in proliferative, but not apoptotic, epithelia l cells. These studies indicate that Xiap is an important element in the co ntrol of ovarian tumor growth and may be a point of regulation for cisplati n in the induction of apoptosis. These results suggest that the ability of cisplatin to down-regulate Xiap content may be an important determinant of chemosensitivity in hOSE cancer.