Communicated by Bruce Gottlieb
Functional Characterization of Novel Mutations Affecting Survivin (BIRC5)-Mediated Therapy Resistance in Head and Neck Cancer Patients
Article first published online: 20 DEC 2012
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 2, pages 395–404, February 2013
How to Cite
Knauer, S. K., Unruhe, B., Karczewski, S., Hecht, R., Fetz, V., Bier, C., Friedl, S., Wollenberg, B., Pries, R., Habtemichael, N., Heinrich, U.-R. and Stauber, R. H. (2013), Functional Characterization of Novel Mutations Affecting Survivin (BIRC5)-Mediated Therapy Resistance in Head and Neck Cancer Patients. Hum. Mutat., 34: 395–404. doi: 10.1002/humu.22249
Contract grant sponsors: MAIFOR; German Research Foundation FKZ KN 973/1-1; Stiftung Tumorforschung Kopf-Hals; Carl-Zeiss foundation 3ChemBioMed2 priority program.
- Issue published online: 29 JAN 2013
- Article first published online: 20 DEC 2012
- Accepted manuscript online: 15 NOV 2012 12:29PM EST
- Manuscript Accepted: 31 OCT 2012
- Manuscript Received: 1 JAN 2012
- German Research Foundation. Grant Number: FKZ KN 973/1-1;
- Stiftung Tumorforschung Kopf-Hals
- Carl-Zeiss foundation
- cisplatin resistance;
- nuclear export;
Survivin (BIRC5) is an acknowledged cancer therapy-resistance factor and overexpressed in head and neck squamous cell carcinomas (HNSCC). Driven by its nuclear export signal (NES), Survivin shuttles between the nucleus and the cytoplasm, and is detectable in both cellular compartments in tumor biopsies. Although predominantly nuclear Survivin is considered a favorable prognostic disease marker for HNSCC patients, the underlying molecular mechanisms are not resolved. Hence, we performed immunohistochemical and mutational analyses using laser capture microdissection on HNSCC biopsies from patients displaying high levels of nuclear Survivin. We found somatic BIRC5 mutations, c.278T>C (p.Phe93Ser), c.292C>T (p.Leu98Phe), and c.288A>G (silent), in tumor cells, but not in corresponding normal tissues. Comprehensive functional characterization of the Survivin mutants by ectopic expression and microinjection experiments revealed that p.Phe93Ser, but not p.Leu98Phe inactivated Survivin's NES, resulted in a predominantly nuclear protein, and attenuated Survivin's dual cytoprotective activity against chemoradiation-induced apoptosis. Notably, in xenotransplantation studies, HNSCC cells containing the p.Phe93Ser mutation responded significantly better to cisplatin-based chemotherapy. Collectively, our results underline the disease relevance of Survivin's nucleocytoplasmic transport, and provide first evidence that genetic inactivation of Survivin's NES may account for predominantly nuclear Survivin and increased therapy response in cancer patients.