Cancer Cell Biology
Inducible NO synthase confers chemoresistance in head and neck cancer by modulating survivin†
Article first published online: 24 NOV 2008
Copyright © 2009 Wiley-Liss, Inc.
International Journal of Cancer
Volume 124, Issue 9, pages 2033–2041, 1 May 2009
How to Cite
Fetz, V., Bier, C., Habtemichael, N., Schuon, R., Schweitzer, A., Kunkel, M., Engels, K., Kovács, A. F., Schneider, S., Mann, W., Stauber, R. H. and Knauer, S. K. (2009), Inducible NO synthase confers chemoresistance in head and neck cancer by modulating survivin. Int. J. Cancer, 124: 2033–2041. doi: 10.1002/ijc.24182
This study is dedicated to Dieter Haupt one of the founders of the Head and Neck Cancer Foundation, who just died of cancer.
- Issue published online: 24 FEB 2009
- Article first published online: 24 NOV 2008
- Manuscript Accepted: 27 OCT 2008
- Manuscript Received: 6 JUL 2008
- Peter und Traudl Engelhorn-
- Priority Program Minimal Invasive Surgery
- Head&Neck Cancer Foundation
- therapy resistance;
- cell cycle;
- nitric oxide;
- chromosomal passenger complex protein
The dual role of the inducible NO synthase (iNOS) and NO signaling in head and neck squamous cell carcinoma (HNSCC) is a complex and can both promote or inhibit tumor progression. However, the underlying molecular mechanisms are not yet resolved in detail. We show for the first time that conditions, favoring low NO levels conferred resistance against cisplatin/taxol-induced apoptosis in HNSCC cell lines. Cytoprotection was mediated by survivin, because we observed its upregulation subsequent to low doses of the NO donors S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) or ectopic expression of physiologic amounts of iNOS. Also, RNAi-mediated depletion of survivin blocked NOs anti-apoptotic effects. Induction of survivin involves activation of the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway, which was antagonized by the PI3K-inhibitor LY294002. Importantly, application of the iNOS-specific inhibitor 1400W combined with RNAi-mediated downregulation of survivin cooperatively enhanced drug-induced cell death. The iNOS/survivin-axis appears to be also of clinical relevance since immunohistochemistry revealed that iNOS expression correlated with enhanced survivin levels in HNSCC specimens. In contrast, high NO concentrations suppressed survivin levels in HNSCC but also in non-malignant cells resulting in apoptosis. Cell death induced by high amounts of SNAP/SNP or by strong overexpression of iNOS involved activation of p38MAP-kinase, which was counteracted by the p38MAP-kinase inhibitor SB202190. Here, we provide evidence for a novel molecular mechanism how NO signaling may contribute to therapy resistance in HNSCC by modulating survivin expression. Our data further suggest pursuing pharmacogenetic iNOS/survivin-targeting approaches as potential therapeutic strategies in head and neck cancer. © 2008 Wiley-Liss, Inc.