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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Tao Zhang, Jeremy Z. Fields, Saundra M. Ehrlich and Bruce M. Boman
Journal of Pharmacology and Experimental Therapeutics February 2004, 308 (2) 434-437; DOI: https://doi.org/10.1124/jpet.103.059378
Tao Zhang
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Jeremy Z. Fields
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Saundra M. Ehrlich
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Bruce M. Boman
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Abstract

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 β-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 β-catenin degradation, which would reduce Tcf-4 activation. This suggests that the β-catenin:Tcf-4:survivin mechanism may be a useful target for therapy or chemoprevention of colon cancer.

Footnotes

  • Research support was provided by the Commonwealth of Pennsylvania (ME-01-329) and CATX Inc., Gladwyne, PA.

  • DOI: 10.1124/jpet.103.059378.

  • ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; FAP, familial adenomatous polyposis; COX, cyclooxygenase; APC, adenomatous polyposis coli; Tcf-4, T-cell factor 4; RT-PCR, reverse transcription-polymerase chain reaction.

    • Received August 30, 2003.
    • Accepted October 14, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 2
1 Feb 2004
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Tao Zhang, Jeremy Z. Fields, Saundra M. Ehrlich and Bruce M. Boman
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 434-437; DOI: https://doi.org/10.1124/jpet.103.059378

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Tao Zhang, Jeremy Z. Fields, Saundra M. Ehrlich and Bruce M. Boman
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 434-437; DOI: https://doi.org/10.1124/jpet.103.059378
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