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.
Lu
Desheng
D
Rebecca and John Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA. delu@ucsd.edu
Cottam
Howard B
HB
Corr
Maripat
M
Carson
Dennis A
DA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017308:Etodolac / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D047495:PPAR gamma / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011485:Protein Binding; D047488:Retinoid X Receptors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D047495:PPAR gamma; D047488:Retinoid X Receptors; D051176:beta Catenin; D017308:Etodolac; D011451:Prostaglandin-Endoperoxide Synthases