Protein kinase C betaII and TGFbetaRII in omega-3 fatty acid-mediated inhibition of colon carcinogenesis.
Increasing evidence demonstrates that protein kinase C betaII (PKCbetaII) promotes colon carcinogenesis. We previously reported that colonic PKCbetaII is induced during colon carcinogenesis in rodents and humans, and that elevated expression of PKCbetaII in the colon of transgenic mice enhances colon carcinogenesis. Here, we demonstrate that PKCbetaII represses transforming growth factor beta receptor type II (TGFbetaRII) expression and reduces sensitivity to TGF-beta-mediated growth inhibition in intestinal epithelial cells. Transgenic PKCbetaII mice exhibit hyperproliferation, enhanced colon carcinogenesis, and marked repression of TGFbetaRII expression. Chemopreventive dietary omega-3 fatty acids inhibit colonic PKCbetaII activity in vivo and block PKCbetaII-mediated hyperproliferation, enhanced carcinogenesis, and repression of TGFbetaRII expression in the colonic epithelium of transgenic PKCbetaII mice. These data indicate that dietary omega-3 fatty acids prevent colon cancer, at least in part, through inhibition of colonic PKCbetaII signaling and restoration of TGF-beta responsiveness.
Murray
Nicole R
NR
Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1048, USA.
Weems
Capella
C
Chen
Lu
L
Leon
Jessica
J
Yu
Wangsheng
W
Davidson
Laurie A
LA
Jamieson
Lee
L
Chapkin
Robert S
RS
Thompson
E Aubrey
EA
Fields
Alan P
AP
D000818:Animals; D002455:Cell Division; D003110:Colonic Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D064546:Protein Kinase C beta; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
D015525:Fatty Acids, Omega-3; D007527:Isoenzymes; D018125:Receptors, Transforming Growth Factor beta; D011493:Protein Kinase C; D064546:Protein Kinase C beta