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J. Biol. Chem., Vol. 278, Issue 13, 11167-11174, March 28, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/13/11167    most recent M211424200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yu, W. Articles by Fields, A. P. Search for Related Content PubMed PubMed Citation Articles by Yu, W. Articles by Fields, A. P. Social Bookmarking                      What's this?

Role of Cyclooxygenase 2 in Protein Kinase C II-mediated Colon Carcinogenesis^*

Wangsheng Yu, Nicole R. Murray, Capella Weems, Lu Chen, Huiping Guo, Richard Ethridge, Jeffrey D. Ceci, B. Mark Evers, E. Aubrey Thompson, and Alan P. Fields

From the Sealy Center for Cancer Cell Biology and the Departments of Pharmacology and Toxicology, Human Biological Chemistry and Genetics and Surgery, The University of Texas Medical Branch, Galveston, Texas 77555-1048

Elevated expression of protein kinase C II (PKCII) 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 PKCII 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-RII) 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 PKCII induces the expression of cyclooxygenase type 2 (Cox-2) in rat intestinal epithelial (RIE) cells in vitro and in transgenic PKCII mice in vivo. Cox-2 mRNA increases more than 10-fold with corresponding increases in Cox-2 protein and PGE2 production in RIE/PKCII cells. PKCII 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-RII both in vitro and in vivo and restores TGF-mediated transcription in RIE/PKCII cells. Likewise, the -3 fatty acid eicosapentaenoic acid (EPA), which inhibits PKCII activity and colon carcinogenesis, causes inhibition of Cox-2 protein expression, re-expression of TGF-RII, and restoration of TGF-1-mediated transcription in RIE/PKCII cells. Our data demonstrate that PKCII promotes colon cancer, at least in part, through induction of Cox-2, suppression of TGF- signaling, and establishment of a TGF--resistant, hyperproliferative state in the colonic epithelium. Our data define a procarcinogenic PKCII  Cox-2  TGF- signaling axis within the colonic epithelium, and provide a molecular mechanism by which dietary -3 fatty acids and nonsteroidal antiinflammatory agents such as Celecoxib suppress colon carcinogenesis.

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