Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB.
Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB.
复制标题
硝基苯乙烯衍生物作为 RXR α 配体抑制 TNF α NF-κ B 激活
DOI：
10.1158/0008-5472.can-14-2435
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发表时间：
2015-05-15
期刊：
影响因子：
11.2
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Zeng Z;Sun Z;Huang M;Zhang W;Liu J;Chen L;Chen F;Zhou Y;Lin J;Huang F;Xu L;Zhuang Z;Guo S;Alitongbieke G;Xie G;Xu Y;Lin B;Cao X;Su Y;Zhang XK;Zhou H
维甲酸X受体α（RXRα）及其N端截短型- tRXRα广泛参与癌症的发展，并代表了癌症预防和治疗的有趣靶点。RXRα和tRXRα的成功操纵需要鉴定其可产生治疗作用的调节剂。本文报道了一类硝基苯乙烯衍生物与RXRα通过一种独特的机制结合，其中硝基苯乙烯衍生物的硝基和RXRα的Cys 432是结合所必需的。该结合导致Gal 4-DBD-RXRα-LBD反式激活的有效激活。然而，这种结合抑制了RXRα同源二聚体的反式激活，这可能是由于这些硝基苯乙烯衍生物诱导的RXRα同源二聚体的独特构象。Cys 432分别被Tyr和Trp取代的两个RXRα点突变体可以模拟两种硝基苯乙烯衍生物的结合，并具有自反式激活的能力。在研究结合的功能后果中，我们发现这些硝基苯乙烯衍生物可以以tRXRα依赖的方式有效地抑制TNFα/NFκB信号通路。tRXRα通过与TRAF 2相互作用促进TNFα诱导的NFκB活化，并增强TNFα诱导的RIP 1泛素化，这被硝基苯乙烯衍生物强烈抑制。硝基苯乙烯衍生物与TNFα联合应用对TNFα诱导的NFκB活化具有协同作用，抑制TNFα诱导的NFκB活化，诱导肿瘤细胞凋亡。总之，我们的结果显示了一类新的RXRα调节剂，通过其独特的结合模式和新的作用机制诱导癌细胞凋亡。
Retinoid X receptor alpha (RXRα) and its N-terminally truncated version - tRXRα are widely implicated in cancer development and represent intriguing targets for cancer prevention and treatment. Successful manipulation of RXRα and tRXRα requires the identification of their modulators that could produce therapeutic effects. Here we report that a class of nitrostyrene derivatives bind to RXRα by a unique mechanism, of which the nitro group of nitrostyrene derivatives and Cys432 of RXRα are required for binding. The binding results in the potent activation of Gal4-DBD-RXRα-LBD transactivation. However, the binding inhibits the transactivation of RXRα homodimer, which might be due to the distinct conformation of RXRα homodimer induced by these nitrostyrene derivatives. Two RXRα point mutants with Cys432 substituted with Tyr and Trp, respectively, could mimic the bindings of two nitrostyrene derivatives and have the ability of auto-transactivation. In studying the functional consequences of the binding, we show that these nitrostyrene derivatives could potently inhibit TNFα/NFκB signaling pathway in a tRXRα dependent manner. tRXRα promotes TNFα-induced NFκB activation through its interacting with TRAF2 and enhancing TNFα-induced ubiquitination of RIP1, which is strongly inhibited by nitrostyrene derivatives. The inhibition of TNFα-induced NFκB activation results in the synergistic effect of the combination of nitrostyrene derivatives and TNFα on the induction of cancer cell apoptosis. Together, our results show a new class of RXRα modulators that induce apoptosis of cancer cells through their unique binding mode and new mechanism of action.