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Reproductive Biology Unit (J.L., Q.F., J.-M.K., D.S., M.L., B.V., B.K.T.) and Division of Gynecologic Oncology (B.V., W.F., M.F.K.F., M.S., B.K.T.), Departments of Obstetrics and Gynecology, Cellular and Molecular Medicine (J.L., D.S., B.V., B.K.T.) and Pathology (M.S.), University of Ottawa; Loeb Health Research Institute (J.L., Q.F., D.S., J.-M.K., M.L., B.K.T.), The Ottawa Hospital (W.F., M.F.K.F., M.S., B.K.T.), ApoptoGen, Inc. (P.L., R.G.K.), and Children’s Hospital of Eastern Ontario, Ottawa Regional Cancer Center (B.V.), Ottawa, Ontario, Canada K1Y 4E9
Address all correspondence and requests for reprints to: Benjamin K. Tsang, Ph.D., Loeb Health Research Institute, The Ottawa Hospital (Civic Campus), 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4E9. E-mail: btsang{at}lri.ca
The inhibitor of apoptosis proteins (IAPs) constitutes a family of highly conserved apoptosis suppressor proteins that were originally identified in baculoviruses. Although IAP homologs have recently been demonstrated to suppress apoptosis in mammalian cells, their expression and role in human ovarian epithelial cancer and chemotherapy resistance are unknown. In the present study we used cisplatin-sensitive and -resistant human ovarian surface epithelial (hOSE) cancer cell lines and adenoviral antisense and sense complementary DNA expression to examine the role of IAP in the regulation of apoptosis in human ovarian cancer cells and chemoresistance. Antisense down-regulation of X-linked inhibitor of apoptosis protein (Xiap), but not human inhibitor of apoptosis protein-2 (Hiap-2), induced apoptosis in cisplatin-sensitive and, to a lesser extent, in -resistant cells. Cisplatin consistently decreased Xiap content and induced apoptosis in the cisplatin-sensitive, but not cisplatin-resistant, cells. Hiap-2 expression was either unaffected or inhibited to a lesser extent. The inhibition of IAP protein expression and induction of apoptosis by cisplatin was time and concentration dependent. Infection of cisplatin-sensitive cells with adenoviral sense Xiap complementary DNA resulted in overexpression of Xiap and markedly attenuated the ability of cisplatin to induce apoptosis. Immunohistochemical localization of the IAPs in hOSE tumors demonstrated the presence of Xiap and Hiap-2, with their levels being highest in proliferative, but not apoptotic, epithelial cells. These studies indicate that Xiap is an important element in the control of ovarian tumor growth and may be a point of regulation for cisplatin 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.
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