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首页> 外文期刊>Cancer Cell >NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling.
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NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling.

机译：NSAID舒林酸及其类似物结合RXRalpha并抑制RXRalpha依赖性AKT信号传导。

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摘要

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anticancer effects through cyclooxygenase-2 (COX-2)-dependent and independent mechanisms. Here, we report that Sulindac, an NSAID, induces apoptosis by binding to retinoid X receptor-alpha (RXRalpha). We identified an N-terminally truncated RXRalpha (tRXRalpha) in several cancer cell lines and primary tumors, which interacted with the p85alpha subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-alpha (TNFalpha) promoted tRXRalpha interaction with the p85alpha, activating PI3K/AKT signaling. When combined with TNFalpha, Sulindac inhibited TNFalpha-induced tRXRalpha/p85alpha interaction, leading to activation of the death receptor-mediated apoptotic pathway. We designed and synthesized a Sulindac analog K-80003, which has increased affinity to RXRalpha but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRalpha-dependent AKT activation and tRXRalpha tumor growth in animals.
机译：非甾体类抗炎药（NSAIDs）通过依赖于环氧合酶2（COX-2）的独立机制发挥其抗癌作用。在这里，我们报道Sulindac，一种NSAID，通过与类维生素A X受体-α（RXRalpha）结合诱导凋亡。我们在几种癌细胞系和原发性肿瘤中鉴定了N末端截短的RXRalpha（tRXRalpha），它们与磷脂酰肌醇3-OH激酶（PI3K）的p85alpha亚基相互作用。肿瘤坏死因子-α（TNFalpha）促进tRXRalpha与p85alpha的相互作用，激活PI3K / AKT信号传导。当与TNFalpha组合时，舒林酸抑制TNFalpha诱导的tRXRalpha / p85alpha相互作用，从而导致死亡受体介导的凋亡途径的激活。我们设计并合成了Sulindac类似物K-80003，它与RXRalpha的亲和力增加，但缺乏COX抑制活性。 K-80003在抑制tRXRalpha依赖的AKT激活和tRXRalpha肿瘤在动物体内生长方面显示出增强的功效。

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