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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

The Chemopreventive Agent Sulindac Attenuates Expression of the Antiapoptotic Protein Survivin in Colorectal Carcinoma Cells

Division of Genetic and Preventive Medicine, Thomas Jefferson University (T.Z., S.M.E., B.M.B.), Philadelphia, Pennsylvania; and CATX Inc., Gladwyne, Pennsylvania (J.Z.F.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac have chemopreventive activity against colorectal tumors. Although the molecular mechanism has not been fully established, it is thought to involve the ability of NSAIDs to induce apoptosis. Because the majority of colon carcinomas are known to overexpress antiapoptotic proteins such as survivin and Bcl-2 and show only limited ability to undergo apoptosis, we hypothesized that the ability of sulindac to cause regression of adenomas and to inhibit colon carcinogenesis is mediated, at least in part, by down-regulation of one or more of these antiapoptotic proteins. To test this hypothesis, we exposed HT-29 colon carcinoma cells to sulindac. Sulindac induced a sustained decrease in mRNA and protein expression for survivin but not for Bcl-2. This finding suggests that sulindac is selectively acting through a survivin-related pathway. This is consistent with our earlier finding that inhibition of the -catenin:T-cell factor 4 (Tcf-4) pathway by the adenomatous polyposis coli protein down-regulates survivin expression and with recent evidence that sulindac induces -catenin degradation, which would reduce Tcf-4 activation. This suggests that the -catenin:Tcf-4:survivin mechanism may be a useful target for therapy or chemoprevention of colon cancer.

Address correspondence to: Dr. Bruce M. Boman, Director, Division of Genetic and Preventive Medicine, Department of Medicine, 1100 Walnut St., Suite 400, Thomas Jefferson University, Philadelphia PA 19107. E-mail: bruce.boman{at}mail.tju.edu

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