Role of Protein Kinase C in Colon Carcinogenesis

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DESCRIPTION (provided by applicant): Colon cancer is the second leading cause of cancer death in the United States. It arises by a multi-step process involving progressive changes in signaling pathways that regulate epithelial cell proliferation, differentiation and survival. PKCbetaII induces hyperproliferation in the colon, and is required for early steps in colon carcinogenesis in vivo. PKCbetaII induces resistance to the growth inhibitory effects of TGFbeta in rat intestinal epithelial (RIE) cells through activation of a novel PKCbetaII->Cox-2->TGFbetaRII signaling axis. PKCbetaII also induces an invasive phenotype in RIE cells through activation of a PKCbetaII->Ras/Mek->PKCI/Rac1 signaling pathway. The overall hypothesis to be tested in this proposal is that PKCbetaII is required for the transformed phenotype in human colon cancer cells. Aim 1 will test the hypothesis that PKCbetaII confers TGFbeta resistance on human colon cancer cells by activating the PKCbetaII->Cox-->?TGFbetaRII signaling axis. Aim 2 will test the hypothesis that PKCbetaII is important for anchorage-independent growth and invasion of human colon cancer cells in vitro, and for tumorigenicity and metastasis in vivo. PKCbetaII expression will also be assessed in human colon cancers and compared with clinical outcome. Aim 3 will test the hypothesis that PKCII is required for K-Ras-mediated colon carcinogenesis in vivo using two complementary transgenic K-Ras mouse models crossed to PKCbeta KO mice. Aim 4 will test the hypothesis that PKCbetaII and PKC/I collaborate to promote colon carcinogenesis in vivo. The role of PKC/I in PKCbetaII-mediated colon carcinogenesis will be assessed in transgenic PKCbetaII mice crossed to transgenic mice expressing kinase-deficient PKC/I. Synergism between PKCbetaII and PKC/I in colon cancer progression, invasion and metastasis will be assessed in transgenic PKCbetaII mice crossed to mice expressing constitutively-active PKC/I. These studies will determine the role of PKCbetaII in human colon cancer cell transformation, the signaling mechanisms by which PKCbeta/II contributes to cellular transformation, and the relationship between PKCbetaII, PKC? and oncogenic K-Ras in promoting colon carcinogenesis in vivo. They will also assess PKCbetaII as a potential therapeutic target and prognostic marker in colon cancer, and develop new genetic models of colon cancer that may be suitable for studying all stages of colon carcinogenesis from initiation to invasive carcinoma in vivo.