Protein kinase C βII and TGFβRII in ω-3 fatty acid–mediated inhibition of colon carcinogenesis

Abstract

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

Evi1 is a survival factor which conveys resistance to both TGFβ- and taxol-mediated cell death via PI3K/AKT

“…Loss of TGFb responsiveness during colon carcinogenesis has been associated with genetic and epigenetic inactivation of the TGFb type II receptor Parsons et al, 1995), Smad mutations (Riggins et al, 1997), oncogenic activation of K-Ras (Higashidani et al, 2003), and induction of protein kinase C-beta II (Murray et al, 2002). However, the possible role of Evi1 in TGFb signaling in colon cancer is poorly understood.…”

Role of Cyclooxygenase 2 in Protein Kinase C βII-mediated Colon Carcinogenesis

“…We have focused our recent efforts on deciphering the role of specific PKC isozymes in the development of colon cancer (5)(6)(7). We have shown that colon carcinogenesis is accompanied by changes in PKC isozyme expression, including a dramatic increase in the level of PKC␤II expression (5).…”

“…These animals exhibit hyperproliferation of the colonic epithelium and enhanced susceptibility to carcinogeninduced carcinogenesis (6). We recently characterized the transforming growth factor ␤ receptor type II (TGF-␤RII) as a target for PKC␤II-mediated transcriptional repression in intestinal epithelial cells and in the colonic epithelium of transgenic PKC␤II mice (7). PKC␤II-induced inhibition of TGF-␤RII renders intestinal epithelial cells insensitive to growth inhibition by TGF-␤ and accounts, at least in part, for the colonic hyperproliferation and increased sensitivity to colon carcinogenesis characteristic of transgenic PKC␤II mice (6,7).…”

“…We recently characterized the transforming growth factor ␤ receptor type II (TGF-␤RII) as a target for PKC␤II-mediated transcriptional repression in intestinal epithelial cells and in the colonic epithelium of transgenic PKC␤II mice (7). PKC␤II-induced inhibition of TGF-␤RII renders intestinal epithelial cells insensitive to growth inhibition by TGF-␤ and accounts, at least in part, for the colonic hyperproliferation and increased sensitivity to colon carcinogenesis characteristic of transgenic PKC␤II mice (6,7). Our studies to date indicate that PKC␤II plays a critical role in the early stages of colon carcinogenesis by inducing the loss of TGF-␤ responsiveness, thereby imposing a hyperproliferative phenotype, two prominent characteristics of colon cancer.…”

“…PKC␤II protein levels are elevated in preneoplastic lesions in the colon, aberrant crypt foci, and are further elevated in colon tumors (5). To determine whether elevated PKC␤II levels contribute to colon carcinogenesis, we developed transgenic PKC␤II mice that express elevated PKC␤II in the colonic epithelium to levels comparable with those observed in carcinogen-induced colon tumors (6,7). These animals exhibit hyperproliferation of the colonic epithelium and enhanced susceptibility to carcinogeninduced carcinogenesis (6).…”