The chemopreventive agent sulindac attenuates expression of the antiapoptotic protein survivin in colorectal carcinoma cells

被引:49
作者
Zhang, T
Fields, JZ
Ehrlich, SM
Boman, BM
机构
[1] Thomas Jefferson Univ, Dept Med, Div Genet & Prevent Med, Philadelphia, PA 19107 USA
[2] CATX Inc, Gladwyne, PA USA
关键词
D O I
10.1124/jpet.103.059378
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 beta-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 beta-catenin degradation, which would reduce Tcf-4 activation. This suggests that the beta-catenin: Tcf-4: survivin mechanism may be a useful target for therapy or chemoprevention of colon cancer.
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页码:434 / 437
页数:4
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