PKC Beta II: A target for colon cancer chemoprevention

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DESCRIPTION (provided by applicant): 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 BII (PKCBll) as a potential target for therapeutic intervention. PKCBll is induced early during colon carcinogenesis. Transgenic mice overexpressing PKCBll in the colonic epithelium exhibit colonic hyperproliferation and increased susceptibility to carcinogen-induced colon carcinogenesis. In contrast, PKCB knockout (PKCBKO) mice are extremely resistant to colon carcinogenesis and re-expression of PKCBll only in the colonic epithelium restores cancer susceptibility. PKCBll stimulates signaling of the Ras-"PKC1/Rac1 -"MEK and Wnt/APC/B-catenin pathways, 2 signaling pathways frequently disregulated in colon cancer. PKCBll also induces Cox-2 expression and suppresses TGF-B signaling. Chemopreventive dietary w-3 fatty acids inhibit colon carcinogenesis, at least in part, through direct inhibition of PKCBll-mediated signaling. This data demonstrates that PKCBll plays a critical, promotive role in colon carcinogenesis and point to PKCBll as an attractive target for the chemoprevention of colon cancer. Because of the critical role of PKCBll plays in colon carcinogenesis, we hypothesize that LY317615, a selective inhibitor of PKCB, will exhibit potent chemopreventive activity in a mouse model of colon carcinogenesis. This hypothesis will be tested through completion of 2 Specific Aims that will determine the effect of LY317615 on 1) PKCBll-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 PKCB inhibitors in the chemoprevention of colon cancer in high-risk patient populations.