NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling.
NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling.
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DOI：
10.1016/j.ccr.2010.04.023
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发表时间：
2010-06-15
期刊：
影响因子：
50.3
通讯作者：
Zhang XK
中科院分区：
文献类型：
--
作者：
Zhou H;Liu W;Su Y;Wei Z;Liu J;Kolluri SK;Wu H;Cao Y;Chen J;Wu Y;Yan T;Cao X;Gao W;Molotkov A;Jiang F;Li WG;Lin B;Zhang HP;Yu J;Luo SP;Zeng JZ;Duester G;Huang PQ;Zhang XK
非甾体类抗炎药（NSAIDs）通过环氧化酶-2（考克斯-2）依赖性和非依赖性机制发挥其抗肿瘤作用。本文报道了非甾体抗炎药舒林酸通过与维甲酸X受体α（RXRα）结合诱导细胞凋亡。我们在几种癌细胞系和原发性肿瘤中发现了一种N端截短的RXRα（tRXRα），它与磷脂酰肌醇-3-OH激酶（PI 3 K）的p85α亚基相互作用。肿瘤坏死因子-α（TNFα）促进tRXRα与p85α的相互作用，激活PI 3 K/AKT信号通路。当与TNFα联合使用时，舒林酸抑制TNFα诱导的tRXRα/p85α相互作用，导致死亡受体介导的凋亡途径激活。我们设计并合成了一个舒林酸类似物K-80003，它对RXRα的亲和力增加，但缺乏考克斯抑制活性。在动物中，K-80003在抑制tRXRα依赖性AKT活化和tRXRα肿瘤生长方面显示出增强的疗效。
Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-cancer 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-α (RXRα). We identified an N-terminally-truncated RXRα (tRXRα) in several cancer cell lines and primary tumors, which interacted with the p85α subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-α (TNFα) promoted tRXRα interaction with the p85α, activating PI3K/AKT signaling. When combined with TNFα, Sulindac inhibited TNFα-induced tRXRα/p85α 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 RXRα but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRα-dependent AKT activation and tRXRα tumor growth in animals.
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