The chemopreventive agent sulindac attenuates expression of the antiapoptotic protein survivin in colorectal carcinoma cells.
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.
Zhang
Tao
T
Division of Genetic and Preventive Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Fields
Jeremy Z
JZ
Ehrlich
Saundra M
SM
Boman
Bruce M
BM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015179:Colorectal Neoplasms / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D013467:Sulindac / Q000494:pharmacology*; D000077022:Survivin; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D000077022:Survivin; D013467:Sulindac