PKC Beta II: A target for colon cancer chemoprevention

Colon cancer is the second leading cause of cancer death in the United States. Our long-term goal is to reduce the impact of colon cancer through the identification and characterization of relevant targets for chemopreventive and chemotherapeutic drugs. To this end, we have identified protein kinase C aII (PKCall) as a potential target for therapeutic intervention. PKCall is induced early during colon carcinogenesis. Transgenic mice overexpressing PKCall in the colonic epithelium exhibit colonic hyperproliferation and increased susceptibility to carcinogen-induced colon carcinogenesis. In contrast, PKCa knockout (PKCaKO) mice are extremely resistant to colon carcinogenesis and re-expression of PKCall only in the colonic epithelium restores cancer susceptibility. PKCall stimulates signaling of the Ras-"PKC1/Rac1 -"MEK and Wnt/APC/a-catenin pathways, two signaling pathways frequently disregulated in colon cancer. PKCall also induces Cox-2 expression and suppresses TGF-a signaling. Chemopreventive dietary w-3 fatty acids inhibit colon carcinogenesis, at least in part, through direct inhibition of PKCall-mediated signaling. These data demonstrate that PKCall plays a critical, promotive role in colon carcinogenesis and point to PKCall as an attractive target for the chemoprevention of colon cancer. Because of the critical role of PKCall plays in colon carcinogenesis, we hypothesize that LY317615, a selective inhibitor of PKCa, will exhibit potent chemopreventive activity in a mouse model of colon carcinogenesis. This hypothesis will be tested through completion of two Specific Aims that will determine the effect of LY317615 on 1) PKCall-mediated gene expression, signaling and cellular homeostasis in vivo and 2) induction of colon carcinogenesis in a preclinical mouse model. Successful completion of the experiments described in this proposal will provide valuable preclinical support for the use of PKCa inhibitors in the chemoprevention of colon cancer in high-risk patient populations.