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.