Caveolin-1 is a novel regulator of K-RAS-dependent migration in colon carcinogenesis

Caveolin-1 is an essential component of membrane caveolae. It is an important regulator of cellular processes such as signal transduction and endocytosis. We report here, for the first time, that caveolin-1 is a target of the K-RAS oncogene in colon carcinogenesis. Caveolin-1 is induced in colon cancer cells and in human colon tumor samples, in response to K-RAS activating mutations. An activated K-RAS oncogene transcriptionally induces caveolin-1 expression in human colon cancer cells and this effect is not restricted to the type of activating K-RAS mutation. Inhibition of the P-I3 Kinase-AKT pathway, but not the ERK MAPK pathway, both important K-RAS effectors, leads to a decrease in caveolin-1 expression indicating that the AKT pathway is involved in caveolin-1 expression in response to an activated K-RAS. Increased AKT signaling induces caveolin-1 expression by increasing the activity of the transcription factor, Sp1. Interestingly; caveolin-1 depletion alters K-RAS-dependent signaling by decreasing Grb2-SOS activity. Consistent with these finding, caveolin-1-depleted cells shows decreased migration in vitro. However, caveolin-1 overexpression by itself does not increase migration whereas an activated Src can increase migration in a caveolin-1-dependent manner. This increased migration is highly dependent on the RhoA GTPase, indicating that an activated K-RAS modulates migration in part via caveolin-1 induction, and increasing RhoA activity via phospho-caveolin-1. Our findings indicate that K-RAS regulates both caveolin-1 expression and other factors affecting caveolin-1 functions in colon cancer-derived cell migration. What's new? The role of the membrane protein caveolin-1 in cancer development has been a subject of controversy. Here the authors report, for the first time, that caveolin-1 is a target of the K-RAS oncogene in colon carcinogenesis. They demonstrate that caveolin-1 is induced in response to mutant K-RAS through AKT activation in colon cancer. They also identify caveolin-1 as a novel activator of K-RAS-dependent signaling and cancer cell migration. The data suggest that caveolin-1 is a conditional "oncogene" in colon cancer whose activity depends on mutant K-RAS, and that a positive feedback loop exists between K-RAS-dependent caveolin-1 expression and signaling. Copyright © 2012 UICC.