Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines.
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/beta-catenin/TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) beta-catenin and beta-catenin/TCF-mediated transcription was investigated. Nuclear beta-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 beta-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear beta-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated beta-catenin/TCF-mediated transcription in the CRC cell lines DLD1 and SW480, and decreased the levels of nonphosphorylated beta-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin D1 were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear beta-catenin localisation and beta-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.
Boon
E M J
EM
Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
Keller
J J
JJ
Wormhoudt
T A M
TA
Giardiello
F M
FM
Offerhaus
G J A
GJ
van der Neut
R
R
Pals
S T
ST
D000236:Adenoma / Q000235:genetics* / Q000503:physiopathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000503:physiopathology; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002467:Cell Nucleus; D002471:Cell Transformation, Neoplastic; D018890:Chemoprevention; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000503:physiopathology; D003598:Cytoskeletal Proteins; D005260:Female; D006801:Humans; D008934:Mitogens; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction; D013467:Sulindac / Q000494:pharmacology*; D015534:Trans-Activators; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D000894:Anti-Inflammatory Agents, Non-Steroidal; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D008934:Mitogens; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D013467:Sulindac