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.