Lu Desheng, Cottam Howard B, Corr Maripat, Carson Dennis A
Rebecca and John Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18567-71. doi: 10.1073/pnas.0509316102. Epub 2005 Dec 13.
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.
Wnt/β-连环蛋白信号通路的激活会促进多种癌症的发展,是化学预防和化学治疗药物的一个有吸引力的靶点。据报道,非甾体抗炎药(NSAIDs)可拮抗β-连环蛋白的功能,但其作用机制尚不清楚。我们在此证明,NSAIDs对β-连环蛋白功能的干扰与环氧化酶(COX)抑制无关。相反,NSAIDs对β-连环蛋白的抑制需要过氧化物酶体增殖物激活受体γ(PPAR-γ)及其共受体视黄酸X受体α(RXR-α)的高水平表达。免疫沉淀实验表明,β-连环蛋白在一些恶性细胞中与RXR-α和PPAR-γ相互作用。因此,NSAIDs对β-连环蛋白依赖性转录的抑制是间接的,并且依赖于其他核受体的共表达。