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

We previously showed that elevated expression of either protein kinase C beta II (PKC beta II) or PKC iota/lambda enhances colon carcinogenesis in mice. Here, we use novel bitransgenic mice to determine the relative importance of PKC beta II and PKC iota/lambda in colon carcinogenesis in two complimentary models of colon cancer in vivo. Bitransgenic mice overexpressing PKC beta II and constitutively active PKC iota (PKC beta II/caPKC iota) or kinase-deficient, dominant-negative PKC iota (PKC beta II/kdPKC iota) 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, PKC beta II/kdPKC iota mice develop predominantly benign colonic adenomas, whereas PKC beta II/caPKC iota mice develop malignant carcinomas. In contrast, PKC beta-deficient (PKC beta(-/-)) mice fail to develop tumors even in the presence of caPKC iota. Our previous data indicated that PKC beta II drives tumorigenesis and proliferation by activating beta-catenin/Ape signaling. Consistent with this conclusion, genetic deletion of PKC beta has no effect on spontaneous tumorigenesis in Apc(min/+) mice. In contrast, tissue-specific knockout of PKC lambda significantly suppresses intestinal tumor formation in Apc(min/+) mice. Our data show that PKC beta II and PKC iota/lambda serve distinct, nonoverlapping functions in colon carcinogenesis. PKC beta II is required for AOM-induced tumorigenesis but is dispensable for tumor formation in Apc(Min/+) mice. PKC iota/lambda promotes tumor progression in both AOM- and Apc(min/+)-induced tumorigenesis. Thus, PKC beta II and PKC iota, 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]