Repression of β-catenin function in malignant cells by nonsteroidal antiinflammatory drugs
Repression of β-catenin function in malignant cells by nonsteroidal antiinflammatory drugs
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DOI：
10.1073/pnas.0509316102
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发表时间：
2005-12-20
影响因子：
11.1
通讯作者：
Carson, DA
中科院分区：
文献类型：
--
作者：
Lu, DS;Cottam, HB;Carson, DA
Wnt/β-catenin途径的激活促进了几种癌症的发展，是化学预防和化疗药物的一个有吸引力的靶点。非甾体抗炎药(NSAIDs)具有拮抗β-连环蛋白功能的作用，但其作用机制尚不清楚。我们在这里证明，非类固醇抗炎药对β-连环蛋白功能的干扰与环氧合酶(COX)抑制无关。相反，非甾体抗炎药抑制p-catenin需要高水平表达过氧化物酶体增殖物激活受体γ(PPAR-γ)及其辅助受体维甲酸-X-受体α(RXR-α)。免疫沉淀实验表明，在某些肿瘤细胞中，β-连环蛋白与RXR-a和PPAR-γ相互作用。因此，非甾体抗炎药对β-连环蛋白依赖的转录的抑制是间接的，并且依赖于其他核受体的共表达。
Activation of the Wnt/beta-catenin pathway promotes the development of several cancers and is an attractive target for chemopreventive and chemotherapeutic agents. Nonsteroidal anti-inflammatory 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 p-catenin requires the high level expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) and its co-receptor retinoid-X-receptor alpha (RXR-alpha). Immunciprecipitation experiments show that beta-catenin interacts with RXR-a 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.