Protein kinase Cbeta 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 CbetaII (PKCbetaII) 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 PKCbetaII is an effective target for colon cancer chemoprevention using enzastaurin (LY317615), a PKCbeta-selective inhibitor, in a mouse model of colon carcinogenesis. We find that enzastaurin potently reduces azoxymethane-induced colon tumor initiation and progression by inhibiting PKCbetaII-mediated tumor cell proliferation and beta-catenin accumulation. Biochemically, enzastaurin reduces expression of the PKCbetaII- and beta-catenin/T-cell factor-regulated genes PKCbetaII, 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, PKCbetaII is an important target for colon cancer chemoprevention and the PKCbeta-selective inhibitor enzastaurin may represent an effective chemopreventive agent in patients at high risk for colon cancer.
Fields
Alan P
AP
Departments of Cancer Biology and Pathology, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
Calcagno
Shelly R
SR
Krishna
Murli
M
Rak
Sofija
S
Leitges
Michael
M
Murray
Nicole R
NR
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000473:pathology* / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D064546:Protein Kinase C beta; D051176:beta Catenin / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D051176:beta Catenin; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C504878:enzastaurin