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

• Published in: The Journal of biological chemistry 2003-03, Vol.278 (13), p.11167
• Main Authors: Wangsheng Yu, Nicole R. Murray, Capella Weems, Lu Chen, Huiping Guo, Richard Ethridge, Jeffrey D. Ceci, B. Mark Evers, E. Aubrey Thompson, Alan P. Fields
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M211424200

Elevated expression of protein kinase C βII (PKCβII) is an early promotive event in colon carcinogenesis (Gokmen-Polar, Y., Murray, N. R., Velasco, M. A., Gatalica, Z., and Fields, A. P. (2001) Cancer Res. 61, 1375–1381). Expression of PKCβII in the colon of transgenic mice leads to hyperproliferation and increased susceptibility to colon carcinogenesis due, at least in part, to repression of transforming growth factor beta type II receptor (TGF-βRII) expression (Murray, N. R., Davidson, L. A., Chapkin, R. S., Gustafson, W. C., Schattenberg, D. G., and Fields, A. P. (1999) J. Cell Biol., 145, 699–711). Here we report that PKCβII induces the expression of cyclooxygenase type 2 (Cox-2) in rat intestinal epithelial (RIE) cells in vitro and in transgenic PKCβII mice in vivo . Cox-2 mRNA increases more than 10-fold with corresponding increases in Cox-2 protein and PGE2 production in RIE/PKCβII cells. PKCβII activates the Cox-2 promoter by 2- to 3-fold and stabilizes Cox-2 mRNA by at least 4-fold. The selective Cox-2 inhibitor Celecoxib restores expression of TGF-βRII both in vitro and in vivo and restores TGFβ-mediated transcription in RIE/PKCβII cells. Likewise, the ω-3 fatty acid eicosapentaenoic acid (EPA), which inhibits PKCβII activity and colon carcinogenesis, causes inhibition of Cox-2 protein expression, re-expression of TGF-βRII, and restoration of TGF-β1-mediated transcription in RIE/PKCβII cells. Our data demonstrate that PKCβII promotes colon cancer, at least in part, through induction of Cox-2, suppression of TGF-β signaling, and establishment of a TGF-β-resistant, hyperproliferative state in the colonic epithelium. Our data define a procarcinogenic PKCβII → Cox-2 → TGF-β signaling axis within the colonic epithelium, and provide a molecular mechanism by which dietary ω-3 fatty acids and nonsteroidal antiinflammatory agents such as Celecoxib suppress colon carcinogenesis.