title: 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 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.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Biochemistry and Molecular and Cellular Biology Graduate Program, University of Arizona, Tucson, AZ, USA.
authors.forename: Upal K
authors.initials: UK
authors.lastname: Basu Roy
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Henkhaus
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.forename: Eugene W
authors.initials: EW
authors.lastname: Gerner
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Ignatenko
mesh_terms: D015153:Blotting, Western; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D020558:GTP Phosphohydrolases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System / Q000235:genetics; D009154:Mutation; D010957:Plasmids; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D016329:Sp1 Transcription Factor; C066737:RHOA protein, human; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases; D016283:Proto-Oncogene Proteins p21(ras); D020742:rhoA GTP-Binding Protein