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 β1-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, β1-integrin or FAK and cholesterol depletion by β-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 3β, 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 β1-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.
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Acknowledgements
We thank M Hiber, B Reincke and G Schröder for excellent technical assistance and M Liscovitch (Weizmann Institute of Science, Israel) for pcDNA3-Cav-1 and control vectors. The work was supported in part by grants from the German Ministry of Education and Research (BMBF Contract 03ZIK041 to NC), by the Deutsche Krebshilfe (70-2937-SaI to RG) as well as a MRC fellowship and RO1 CA73820 to EJB.
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Cordes, N., Frick, S., Brunner, T. et al. Human pancreatic tumor cells are sensitized to ionizing radiation by knockdown of caveolin-1. Oncogene 26, 6851–6862 (2007). https://doi.org/10.1038/sj.onc.1210498
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DOI: https://doi.org/10.1038/sj.onc.1210498
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