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 coreceptor 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. peroxisome proliferator-activated receptor [gamma] | retinoid X receptor [alpha]