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

Abstract

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 over-expression 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.

Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels

“…Together these findings are consistent with a model in which K-Ras activation drives the up-regulation of activated eIF5A, which in turn, promotes Rho/ROCK expression, leading to cytoskeletal reorganization as well as other pro-tumorigenic and pro-survival programs necessary for cancer metastasis. In support of this model, K-Ras has been shown to stimulate RhoA/ROCK signaling to promote tumor cell survival and metastasis (43)(44)(45)(46). However, K-Ras-induced eIF5A expression also likely contributes to tumor metastasis by modulating the expression levels of other key signaling/cytoskeletal proteins including PEAK1 (pseudopodium-enriched atypical kinase 1), which is critically involved in PDAC progression (13).…”

Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells

“…[25][26][27] Previous study showed let-7 is complementary to multiple sequences in the 3 0 UTR of human RAS genes, and represses its expression. 28 NF-kB can act as downstream of Ras pathway.…”

Caveolin-1 Expression is Associated with Tumor Size and Therapy Response in Wilms Tumor

“…11,12 These findings reveal an unexpected role for WT1 as a key regulator of the genetic network of oncogenic K-RAS and provide important insight into the mechanisms that regulate proliferation in response to oncogenic signals. [11][12][13][14] In the present study, molecular genetics analyses were not performed and this is a limitation of the study. Therefore we don't know the WT1 gene status of the patients.…”

“…Previous studies showed that Cav1 facilitate both ERK and AKT signaling in cancer cells from kidney, ovary, colon, prostate, epidermis, muscle, brain and is associated with promoting cell invasion, proliferation, angiogenesis and multi-drug resistance. [12][13][14][15][16][17][18][19][20] Most authors suggested that Cav-1 positive tumor cells served as tumor promoters by these signaling pathways. 3,[12][13][14][15][16][17][18][19] In the present study, we determined Cav-1 expression nearly in the half of tumors.…”

“…Recent studies have also focused their attention on Cav-1 expression in the peritumoral stromal cells rather than Cav-1 expression in the tumor cells. [12][13][14][15][16][17] For example Goetz et al suggest that there may be an important role for stromal Cav-1 in promoting tumor progression and metastasis. 20 But in the most other studies, loss of stromal Cav-1 expression in association with the high tumoral Cav-1 expression, has been reported to be closely related with poor outcome in different malignancies.…”