Protein kinase C betaII and PKCiota/lambda: collaborating partners in colon cancer promotion and progression.
We previously showed that elevated expression of either protein kinase CbetaII (PKCbetaII) or PKCiota/lambda enhances colon carcinogenesis in mice. Here, we use novel bitransgenic mice to determine the relative importance of PKCbetaII and PKCiota/lambda in colon carcinogenesis in two complimentary models of colon cancer in vivo. Bitransgenic mice overexpressing PKCbetaII and constitutively active PKCiota (PKCbetaII/caPKCiota) or kinase-deficient, dominant-negative PKCiota (PKCbetaII/kdPKCiota) 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, PKCbetaII/kdPKCiota mice develop predominantly benign colonic adenomas, whereas PKCbetaII/caPKCiota mice develop malignant carcinomas. In contrast, PKCbeta-deficient (PKCbeta(-/-)) mice fail to develop tumors even in the presence of caPKCiota. Our previous data indicated that PKCbetaII drives tumorigenesis and proliferation by activating beta-catenin/Apc signaling. Consistent with this conclusion, genetic deletion of PKCbeta has no effect on spontaneous tumorigenesis in Apc(min/+) mice. In contrast, tissue-specific knockout of PKClambda significantly suppresses intestinal tumor formation in Apc(min/+) mice. Our data show that PKCbetaII and PKCiota/lambda serve distinct, nonoverlapping functions in colon carcinogenesis. PKCbetaII is required for AOM-induced tumorigenesis but is dispensable for tumor formation in Apc(Min/+) mice. PKCiota/lambda promotes tumor progression in both AOM- and Apc(min/+)-induced tumorigenesis. Thus, PKCbetaII and PKCiota, whose expression is elevated in both rodent and human colon tumors, collaborate to drive colon tumor formation and progression, respectively.
Murray
Nicole R
NR
Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
Weems
Justin
J
Braun
Ursula
U
Leitges
Michael
M
Fields
Alan P
AP
D000236:Adenoma / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D017491:Genes, APC; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D000099293:Protein Kinase C-lambda
D001397:Azoxymethane; D002273:Carcinogens; D007527:Isoenzymes; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D000099293:Protein Kinase C-lambda