title: NO signaling confers cytoprotectivity through the survivin network in ovarian carcinomas.
abstract: 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.
authors.affiliation: Department of Pathology, University Hospital of Frankfurt, Frankfurt, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Engels
authors.forename: Shirley K
authors.initials: SK
authors.lastname: Knauer
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.forename: Verena
authors.initials: V
authors.lastname: Fetz
authors.forename: Philipp
authors.initials: P
authors.lastname: Harter
authors.forename: Andrea
authors.initials: A
authors.lastname: Schweitzer
authors.forename: Annette
authors.initials: A
authors.lastname: Fisseler-Eckhoff
authors.forename: Friedrich
authors.initials: F
authors.lastname: Kommoss
authors.forename: Lars
authors.initials: L
authors.lastname: Hanker
authors.forename: Valentina
authors.initials: V
authors.lastname: Nekljudova
authors.forename: Iris
authors.initials: I
authors.lastname: Hermanns
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kleinert
authors.forename: Wolf
authors.initials: W
authors.lastname: Mann
authors.forename: Andreas
authors.initials: A
authors.lastname: du Bois
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stauber
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D048051:p38 Mitogen-Activated Protein Kinases