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NO signaling confers cytoprotectivity through the survivin network in ovarian carcinomas

Knut Engels1, Shirley K Knauer, Sibylle Loibl

  • 1Department of Pathology, University Hospital of Frankfurt, Frankfurt, Germany.

Cancer Research
|July 3, 2008
PubMed

Insights

Nitric oxide (NO) has a dual role in ovarian cancer, suppressing survivin at high levels to induce apoptosis but promoting resistance at low levels by upregulating survivin. Targeting iNOS and survivin may improve epithelial ovarian cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Epithelial ovarian cancer (EOC) treatment is hindered by therapy resistance.
  • Survivin, an apoptosis inhibitor and mitotic regulator, impacts EOC outcomes.
  • Mechanisms of survivin dysregulation in EOC require further elucidation.

Purpose of the Study:

  • To investigate the role of nitric oxide (NO) signaling in regulating survivin expression and apoptosis in ovarian cancer cells.
  • To explore the molecular pathways involved in NO-mediated survivin modulation.
  • To assess the clinical relevance of the iNOS/survivin interplay in EOC.

Main Methods:

  • Treatment of ovarian cancer cell lines (OCCs) with NO donors (SNAP, SNP) and iNOS overexpression/inhibition.
  • Assessment of survivin levels, apoptosis, and signaling pathways (p38MAPK, PI3K/Akt).
  • RNA interference (RNAi) for survivin depletion and immunohistochemistry on patient samples.

Main Results:

  • High NO levels or iNOS suppressed survivin via p38MAPK, inducing apoptosis.
  • Low NO concentrations or iNOS upregulated survivin, conferring resistance to carboplatin/paclitaxel.
  • Survivin upregulation by NO involved PI3K/Akt activation.
  • iNOS inhibition combined with survivin depletion enhanced drug-induced apoptosis.
  • Low iNOS correlated with survivin expression in EOC patients, associated with progression risk.

Conclusions:

  • NO signaling exhibits a context-dependent role in EOC apoptosis and therapy resistance via survivin modulation.
  • The PI3K/Akt and p38MAPK pathways mediate NO's effects on survivin.
  • iNOS and survivin expression are clinically relevant biomarkers in EOC.
  • Targeting the iNOS/survivin axis presents a potential therapeutic strategy for EOC.

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