期刊
ONCOGENE
卷 26, 期 48, 页码 6851-6862出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210498
关键词
caveolin-1; ionizing radiation; beta 1-integrin; FAK; pancreatic cancer
资金
- MRC [G0700730] Funding Source: UKRI
- Medical Research Council [G0700730] Funding Source: researchfish
- Medical Research Council [G0700730] Funding Source: Medline
- NCI NIH HHS [R01 CA73820] Funding Source: Medline
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 beta 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 Panel cell lines. The cell lines showed significant radio-sensitization after knockdown of Cav-1, beta 1-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 3 beta, 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 beta 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.
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