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Protein kinase C ßII and TGFßRII in -3 fatty acid–mediated inhibition of colon carcinogenesis

¹ Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, TX 77555
² Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77555
³ Department of Pharmacology, University of Texas Medical Branch, Galveston, TX 77555
⁴ Molecular and Cell Biology Section, Faculty of Nutrition, Texas A&M University, College Station, TX 77843

Address correspondence to Alan P. Fields, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1048. Tel.: (409) 747-1935. Fax: (409) 747-1938. E-mail: afields{at}utmb.edu

Încreasing evidence demonstrates that protein kinase C ßII (PKCßII) promotes colon carcinogenesis. We previously reported that colonic PKCßII is induced during colon carcinogenesis in rodents and humans, and that elevated expression of PKCßII in the colon of transgenic mice enhances colon carcinogenesis. Here, we demonstrate that PKCßII represses transforming growth factor ß receptor type II (TGFßRII) expression and reduces sensitivity to TGF-ß–mediated growth inhibition in intestinal epithelial cells. Transgenic PKCßII mice exhibit hyperproliferation, enhanced colon carcinogenesis, and marked repression of TGFßRII expression. Chemopreventive dietary -3 fatty acids inhibit colonic PKCßII activity in vivo and block PKCßII-mediated hyperproliferation, enhanced carcinogenesis, and repression of TGFßRII expression in the colonic epithelium of transgenic PKCßII mice. These data indicate that dietary -3 fatty acids prevent colon cancer, at least in part, through inhibition of colonic PKCßII signaling and restoration of TGF-ß responsiveness.

Key Words: protein kinase C; colon carcinogenesis; -3 fatty acids; transforming growth factor ß; hyperproliferation

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