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NO Signaling Confers Cytoprotectivity through the Survivin Network in Ovarian Carcinomas

Departments of ¹ Pathology and ² Gynecology and Obstetrics, University Hospital of Frankfurt, Frankfurt, Germany; ³ Molecular and Cellular Oncology and Departments of ⁴ Pathology and ⁵ Pharmacology, University Hospital of Mainz, Mainz, Germany; ⁶ German Breast Group Forschungs GmbH, Neu-Isenburg, Germany; ⁷ Department of Gynecology and Gynecologic Oncology and ⁸ Department for Pathology and Cytology, Dr. Horst Schmidt Klinik, Wiesbaden, Germany; and ⁹ Department for Pathology, University of Mannheim, Mannheim, Germany

Requests for reprints: Roland H. Stauber, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany. Phone: 49-6131-177002; Fax: 49-6131-176671; E-mail: rstauber{at}uni-mainz.de.

Key Words: apoptosis • IAP • therapy resistance

Despite considerable success in the treatment of epithelial ovarian cancer (EOC), therapy resistance counteracts improvement of long-term survival. The dual role of survivin as an apoptosis inhibitor and mitotic regulator has been associated with disease outcome. However, the molecular mechanisms involved in the deregulated expression in EOC of survivin need further investigation. Here, we show that high amounts of the nitric oxide (NO) donors, S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) or strong overexpression of the inducible nitric oxide synthase (iNOS) suppressed survivin levels via the p38MAPK pathway and triggered apoptosis in ovarian cancer cell lines (OCC). Importantly, low NO concentrations conferred resistance against carboplatin/paclitaxel-induced apoptosis. Cytoprotection was mediated by survivin because we observed its up-regulation subsequent to low SNAP/SNP doses or ectopic expression of low amounts of iNOS. Also, RNAi-mediated depletion of survivin blocked the antiapoptotic effects of NO signaling. Induction of survivin involves activation of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway, which was antagonized by the PI3K-inhibitor, LY294002. Interestingly, application of the iNOS-inhibitor 1400W together with RNAi-mediated survivin down-regulation cooperatively enhanced drug-induced apoptosis in OCCs. The iNOS/survivin interdependencies seem to be also of clinical relevance because immunohistochemistry revealed that low iNOS levels correlate with survivin expression (P < 0.01) in carboplatin/paclitaxel-treated EOC patients with minimal postoperative residual tumor (n = 54). Also, iNOS and survivin expression were associated with increased risk for disease progression. Our study uncovers a novel molecular mechanism of how NO signaling may contribute to therapy resistance in EOC by modulating survivin expression. Pharmacogenetic iNOS/survivin-targeting strategies may hence be pursued to complement current treatment modalities in EOC. [Cancer Res 2008;68(13):5159–65]