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Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18567-71. Epub 2005 Dec 13.

Repression of beta-catenin function in malignant cells by nonsteroidal antiinflammatory drugs.

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  • 1Rebecca and John Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA. delu@ucsd.edu

Abstract

Activation of the Wnt/beta-catenin pathway promotes the development of several cancers and is an attractive target for chemopreventive and chemotherapeutic agents. Nonsteroidal antiinflammatory drugs (NSAIDs) have been reported to antagonize beta-catenin function, but their mechanism of action is not known. We demonstrate here that interference with beta-catenin function by NSAIDs does not correlate with cyclooxygenase (COX) inhibition. Instead, NSAID inhibition of beta-catenin requires the high level expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) and its co-receptor retinoid-X-receptor alpha (RXR-alpha). Immunoprecipitation experiments show that beta-catenin interacts with RXR-alpha and PPAR-gamma in some malignant cells. Repression of beta-catenin-dependent transcription by NSAIDs is thus indirect and depends on the coexpression of other nuclear receptors.

PMID:
16352713
[PubMed - indexed for MEDLINE]
PMCID:
PMC1317972
Free PMC Article
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