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Protein Kinase C βII and PKC/: Collaborating Partners in Colon Cancer Promotion and Progression

¹ Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, Florida and ² The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway

Requests for reprints: Alan P. Fields, Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 212, 4500 San Pablo Road, Jacksonville, FL 32224. Phone: 904-953-6109; Fax: 904-953-6233; E-mail: fields.alan{at}mayo.edu.

Key Words: colon carcinogenesis • transgenic mice • β-catenin • proliferation • Adenomatous polyposis coli (Apc) • intestinal tumorigenesis

We previously showed that elevated expression of either protein kinase CβII (PKCβII) or PKC/ enhances colon carcinogenesis in mice. Here, we use novel bitransgenic mice to determine the relative importance of PKCβII and PKC/ in colon carcinogenesis in two complimentary models of colon cancer in vivo. Bitransgenic mice overexpressing PKCβII and constitutively active PKC (PKCβII/caPKC) or kinase-deficient, dominant-negative PKC (PKCβII/kdPKC) in the colon exhibit a similar increase in colon tumor incidence, tumor size, and tumor burden in response to azoxymethane (AOM) when compared with nontransgenic littermates. However, PKCβII/kdPKC mice develop predominantly benign colonic adenomas, whereas PKCβII/caPKC mice develop malignant carcinomas. In contrast, PKCβ-deficient (PKCβ^–/–) mice fail to develop tumors even in the presence of caPKC. Our previous data indicated that PKCβII drives tumorigenesis and proliferation by activating β-catenin/Apc signaling. Consistent with this conclusion, genetic deletion of PKCβ has no effect on spontaneous tumorigenesis in Apc^min/+ mice. In contrast, tissue-specific knockout of PKC significantly suppresses intestinal tumor formation in Apc^min/+ mice. Our data show that PKCβII and PKC/ serve distinct, nonoverlapping functions in colon carcinogenesis. PKCβII is required for AOM-induced tumorigenesis but is dispensable for tumor formation in Apc^Min/+ mice. PKC/ promotes tumor progression in both AOM- and Apc^min/+-induced tumorigenesis. Thus, PKCβII and PKC, whose expression is elevated in both rodent and human colon tumors, collaborate to drive colon tumor formation and progression, respectively. [Cancer Res 2009;69(2):656–62]

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