1. ¹OncoRay – Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden, University of Technology, Dresden, Germany
2. ²Bundeswehr Institute of Radiobiology, Munich, Germany
3. ³Radiation Oncology, University Erlangen-Nürnberg, Erlangen, Germany
4. ⁴Departments of Visceral-, Thoracic- and Vascular Surgery, University Hospital, Dresden, Dresden, Germany
5. ⁵Department of Pathology, University Hospital of Kiel, Kiel, Germany
6. ⁶Radiation Oncology and Biology, University of Oxford, Radiobiology Research Institute, Churchill Hospital, Headington, Oxford, UK

Correspondence: Dr N Cordes, OncoRay – Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Fetscherstrasse 74/PF 86, 01307 Dresden, Germany. E-mail: nils.cordes@oncoray.de

Received 12 January 2007; Revised 28 March 2007; Accepted 29 March 2007; Published online 30 April 2007.

Abstract

Caveolin-1 (Cav-1) is an integral transmembrane protein and a critical component in interactions of integrin receptors with cytoskeleton-associated and signaling molecules. Since integrin-mediated cell adhesion generates signals conferring radiation resistance, we examined the effects of small interfering RNA-mediated knockdown of Cav-1 alone or in combination with 1-integrin or focal adhesion kinase (FAK) on radiation survival and proliferation of pancreatic carcinoma cell lines. Irradiation induced Cav-1 expression in PATU8902, MiaPaCa2 and Panc1 cell lines. The cell lines showed significant radiosensitization after knockdown of Cav-1, 1-integrin or FAK and cholesterol depletion by -cyclodextrin relative to nonspecific controls. Under knockdown conditions, proliferation of non-irradiated and irradiated cells was significantly attenuated relative to controls. These findings correlated with changes in expression or phosphorylation of Akt, glycogen synthase kinase 3, Paxillin, Src, c-Jun N-terminal kinase and mitogen-activated protein kinase. Analysis of DNA microarray data revealed a Cav-1 overexpression in a subset of pancreatic ductal adenocarcinoma samples. The data presented show, for the first time, that disruption of interactions of Cav-1 with 1-integrin or FAK affects radiation survival and proliferation of pancreatic carcinoma cells and suggest that Cav-1 is critical to these processes. These results indicate that strategies targeting Cav-1 may be useful as an approach to improve conventional therapies, including radiotherapy, for pancreatic cancer.