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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 beta1-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, beta1-integrin or FAK and cholesterol depletion by beta-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 3beta, 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 beta1-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.

Original publication

DOI

10.1038/sj.onc.1210498

Type

Journal article

Journal

Oncogene

Publication Date

18/10/2007

Volume

26

Pages

6851 - 6862

Keywords

Blotting, Western, Caveolin 1, Cell Adhesion, Cell Cycle, Cell Proliferation, Colony-Forming Units Assay, Fluorescent Antibody Technique, Focal Adhesion Kinase 1, Gene Expression Profiling, Humans, Integrin beta1, Mitogen-Activated Protein Kinases, Pancreatic Neoplasms, Paxillin, Phosphatidylinositol 3-Kinases, Phosphorylation, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins pp60(c-src), RNA, Small Interfering, Radiation Tolerance, Signal Transduction, X-Rays