Protein Kinase Cβ Is an Effective Target for Chemoprevention of Colon Cancer

Colon cancer develops over a period of 10 to 15 years, providing a window of opportunity for chemoprevention and early intervention. However, few molecular targets for effective colon cancer chemoprevention have been characterized and validated. Protein kinase C beta II (PKC beta II) plays a requisite role in the initiation of colon carcinogenesis in a preclinical mouse model by promoting proliferation and increased beta-catenin accumulation. In this study, we test the hypothesis that PKC beta II is an effective target for colon cancer chemoprevention using enzastaurin (LY317615), a PKC beta-selective inhibitor, in a mouse model of colon carcinogenesis. We find that enzastaurin potently reduces azoxymethane-induced colon tumor initiation and progression by inhibiting PKC beta II-mediated tumor cell proliferation and beta-catenin accumulation. Biochemically, enzastaurin reduces expression of the PKC beta II- and beta-catenin/T-cell factor-regulated genes PKC beta II, cyclooxygenase II, and vascular endothelial growth factor, three genes implicated in colon carcinogenesis. Our results show that enzastaurin is an effective chemopreventive agent in a mouse model of sporadic colon cancer that significantly reduces both tumor initiation and progression by inhibiting expression of proproliferative genes. Thus, PKC beta II is an important target for colon cancer chemoprevention and the PKC beta-selective inhibitor enzastaurin may represent an effective chemopreventive agent in patients at high risk for colon cancer. [Cancer Res 2009;69(4):1643-50]