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

Departments of ¹ Cancer Biology and ² Pathology, Mayo Clinic College of Medicine, Jacksonville, Florida and ³ Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway

Requests for reprints: Nicole R. Murray, Department of Cancer Biology, Mayo Clinic College of Medicine-Jacksonville, Room 213, Griffin Cancer Building, 4500 San Pablo Road, Jacksonville, FL 32224. Phone: 904-953-6108; Fax: 904-953-6233; E-mail: murray.nicole{at}mayo.edu.

Key Words: colon • carcinogenesis • chemoprevention • mice • PKCβII • Enzastaurin • AOM

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 CβII (PKCβII) plays a requisite role in the initiation of colon carcinogenesis in a preclinical mouse model by promoting proliferation and increased β-catenin accumulation. In this study, we test the hypothesis that PKCβII is an effective target for colon cancer chemoprevention using enzastaurin (LY317615), a PKCβ-selective inhibitor, in a mouse model of colon carcinogenesis. We find that enzastaurin potently reduces azoxymethane-induced colon tumor initiation and progression by inhibiting PKCβII-mediated tumor cell proliferation and β-catenin accumulation. Biochemically, enzastaurin reduces expression of the PKCβII- and β-catenin/T-cell factor–regulated genes PKCβII, 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, PKCβII is an important target for colon cancer chemoprevention and the PKCβ-selective inhibitor enzastaurin may represent an effective chemopreventive agent in patients at high risk for colon cancer. [Cancer Res 2009;69(4):1643–50]