Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines

E. M.J. Boon, J. J. Keller, T. A.M. Wormhoudt, F. M. Giardiello, G. J.A. Offerhaus, R. Van Der Neut, S. T. Pals

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Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive potential against colorectal carcinomas (CRCs). Inhibition of cyclooxygenase (COX)-2 underlies part of this effect, although COX-2-independent mechanisms may also exist. Nonsteroidal anti-inflammatory drugs appear to inhibit the initial stages of the adenoma-carcinoma sequence, suggesting a link to the APC/β-catenin/ TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) β-catenin and β-catenin/TCF-mediated transcription was investigated. Nuclear β-catenin expression was assessed in pretreatment colorectal adenomas and in adenomas after treatment with sulindac from five patients with familial adenomatous polyposis (FAP). Also, the effect of sulindac sulphide on β-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear β-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated β-catenin/TCF-mediated transcription in the CRC cell lines DLDI and SW480, and decreased the levels of nonphosphorylated β-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin DI were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear β-catenin localisation and β-catenin/TCF-regulated transcription of target genes can be inhibited by sulindac. The inhibition of Wnt-signalling provides an explanation for the COX-2-independent mechanism of chemoprevention by NSAIDs.

Original languageEnglish
Pages (from-to)224-229
Number of pages6
JournalBritish journal of cancer
Volume90
Issue number1
DOIs
Publication statusPublished - 12 Jan 2004

Keywords

  • FAP
  • Sulindac
  • TCF

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