Yu Wangsheng, Murray Nicole R, Weems Capella, Chen Lu, Guo Huiping, Ethridge Richard, Ceci Jeffrey D, Evers B Mark, Thompson E Aubrey, Fields Alan P
Sealy Center for Cancer Cell Biology and the Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas 77555-1048, USA.
J Biol Chem. 2003 Mar 28;278(13):11167-74. doi: 10.1074/jbc.M211424200. Epub 2002 Dec 11.
Elevated expression of protein kinase C beta II (PKC beta II) 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 PKC beta II 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-beta 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 PKC beta II induces the expression of cyclooxygenase type 2 (Cox-2) in rat intestinal epithelial (RIE) cells in vitro and in transgenic PKC beta II mice in vivo. Cox-2 mRNA increases more than 10-fold with corresponding increases in Cox-2 protein and PGE2 production in RIE/PKC beta II cells. PKC beta II 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-beta RII both in vitro and in vivo and restores TGF beta-mediated transcription in RIE/PKC beta II cells. Likewise, the omega-3 fatty acid eicosapentaenoic acid (EPA), which inhibits PKC beta II activity and colon carcinogenesis, causes inhibition of Cox-2 protein expression, re-expression of TGF-beta RII, and restoration of TGF-beta1-mediated transcription in RIE/PKC beta II cells. Our data demonstrate that PKC beta II promotes colon cancer, at least in part, through induction of Cox-2, suppression of TGF-beta signaling, and establishment of a TGF-beta-resistant, hyperproliferative state in the colonic epithelium. Our data define a procarcinogenic PKC beta II --> Cox-2 --> TGF-beta signaling axis within the colonic epithelium, and provide a molecular mechanism by which dietary omega-3 fatty acids and nonsteroidal antiinflammatory agents such as Celecoxib suppress colon carcinogenesis.
蛋白激酶CβII（PKCβII）的表达升高是结肠癌发生过程中的早期促进事件（Gokmen-Polar，Y.，Murray，N. R.，Velasco，M. A.，Gatalica，Z.，以及Fields，A. P.（2001年）《癌症研究》61卷，1375 - 1381页）。PKCβII在转基因小鼠结肠中的表达导致过度增殖，并增加对结肠癌发生的易感性，至少部分原因是转化生长因子βII型受体（TGF-βRII）表达受到抑制（Murray，N. R.，Davidson，L. A.，Chapkin，R. S.，Gustafson，W. C.，Schattenberg，D. G.，以及Fields，A. P.（1999年）《细胞生物学杂志》，145卷，699 - 711页）。在此我们报告，PKCβII在体外大鼠肠上皮（RIE）细胞以及体内转基因PKCβII小鼠中诱导环氧合酶2型（Cox-2）的表达。在RIE/PKCβII细胞中，Cox-2 mRNA增加超过10倍，同时Cox-2蛋白和前列腺素E2（PGE2）的产生相应增加。PKCβII使Cox-2启动子激活2至3倍，并使Cox-2 mRNA稳定至少4倍。选择性Cox-2抑制剂塞来昔布在体外和体内均能恢复TGF-βRII的表达，并在RIE/PKCβII细胞中恢复TGF-β介导的转录。同样，抑制PKCβII活性和结肠癌发生的ω-3脂肪酸二十碳五烯酸（EPA），会导致RIE/PKCβII细胞中Cox-2蛋白表达受到抑制、TGF-βRII重新表达以及TGF-β1介导的转录恢复。我们的数据表明，PKCβII至少部分通过诱导Cox-2、抑制TGF-β信号传导以及在结肠上皮中建立TGF-β抗性的过度增殖状态来促进结肠癌。我们的数据定义了结肠上皮内一个促癌的PKCβII→Cox-2→TGF-β信号轴，并提供了一种分子机制，通过该机制膳食ω-3脂肪酸和非甾体抗炎药如塞来昔布可抑制结肠癌发生。
