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

2005; National Academy of Sciences; Volume: 102; Issue: 51 Linguagem: Inglês

10.1073/pnas.0509316102

1091-6490

Desheng Lu, Howard B. Cottam, Maripat Corr, Dennis A. Carson,

Peroxisome Proliferator-Activated Receptors

Activation of the Wnt/β-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 β-catenin function, but their mechanism of action is not known. We demonstrate here that interference with β-catenin function by NSAIDs does not correlate with cyclooxygenase (COX) inhibition. Instead, NSAID inhibition of β-catenin requires the high level expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and its co-receptor retinoid-X-receptor α (RXR-α). Immunoprecipitation experiments show that β-catenin interacts with RXR-α and PPAR-γ in some malignant cells. Repression of β-catenin-dependent transcription by NSAIDs is thus indirect and depends on the coexpression of other nuclear receptors.