| First Author | Volonte D | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 5 | Pages | 1794-1809 |
| PubMed ID | 29247004 | Mgi Jnum | J:258460 |
| Mgi Id | MGI:6117609 | Doi | 10.1074/jbc.M117.815902 |
| Citation | Volonte D, et al. (2018) Caveolin-1 promotes the tumor suppressor properties of oncogene-induced cellular senescence. J Biol Chem 293(5):1794-1809 |
| abstractText | Oncogene-induced senescence (OIS) is considered a powerful tumor suppressor mechanism. Caveolin-1 acts as a scaffolding protein to functionally regulate signaling molecules. We demonstrate that a lack of caveolin-1 expression inhibits oncogenic K-Ras (K-Ras(G12V))-induced premature senescence in mouse embryonic fibroblasts and normal human bronchial epithelial cells. Oncogenic K-Ras induces senescence by limiting the detoxification function of MTH1. We found that K-Ras(G12V) promotes the interaction of caveolin-1 with MTH1, which results in inhibition of MTH1 activity. Lung cancer cells expressing oncogenic K-Ras have bypassed the senescence barrier. Interestingly, overexpression of caveolin-1 restores cellular senescence in both A549 and H460 lung cancer cells and inhibits their transformed phenotype. In support of these findings, our in vivo data demonstrate that overexpression of oncogenic K-Ras (K-Ras(G12D)) induces cellular senescence in the lung of wildtype but not caveolin-1-null mice. A lack of K-Ras(G12D)-induced premature senescence in caveolin-1-null mice results in the formation of more abundant lung tumors. Consistent with these data, caveolin-1-null mice overexpressing K-Ras(G12D) display accelerated mortality. Finally, our animal data were supported by human sample analysis in which we show that caveolin-1 expression is dramatically down-regulated in lung adenocarcinomas from lung cancer patients, both at the mRNA and protein levels, and that low caveolin-1 expression is associated with poor survival. Together, our data suggest that lung cancer cells escape oncogene-induced premature senescence through down-regulation of caveolin-1 expression to progress from premalignant lesions to cancer. |
