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

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.