Targeting truncated retinoid X receptor-α by CF31 induces TNF-α-dependent apoptosis.
Targeting truncated retinoid X receptor-α by CF31 induces TNF-α-dependent apoptosis.
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DOI：
10.1158/0008-5472.can-12-2038
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发表时间：
2013-01-01
期刊：
影响因子：
11.2
通讯作者：
Zhang XK
中科院分区：
文献类型：
--
作者：
Wang GH;Jiang FQ;Duan YH;Zeng ZP;Chen F;Dai Y;Chen JB;Liu JX;Liu J;Zhou H;Chen HF;Zeng JZ;Su Y;Yao XS;Zhang XK
截断的类视黄醇X受体-α (tRXRα)通过激活PI3K/AKT通路促进癌细胞存活。然而，靶向trxr α-介导的生存通路用于癌症治疗仍有待探索。我们在此报道我们鉴定了一种新的天然产物分子，CF31，一种从台湾克拉托克菌中分离出来的山酮。Pruniflorum，及其调控trxr α-介导的PI3K/AKT通路的生物学评价。CF31结合RXRα，抑制RXRα的转激活。通过RXRα突变分析和计算研究，我们发现，已知与某些RXRα配体（如9-顺式维甲酸（9-顺式ra））形成盐桥的RXRα的Arg316不是CF31拮抗剂作用所必需的，显示出不同的结合模式。对几种CF31类似物的评价表明，拮抗剂作用主要是由于干扰RXRα中螺旋H12的Leu451。CF31是多种癌细胞系中AKT激活的有效抑制剂。与TNFα联用时，通过抑制TNFα诱导的tRXRα与PI3K的p85α调控亚基的相互作用，抑制TNFα对AKT的激活。CF31抑制TNFα活化AKT也导致TNFα依赖性的caspase-8活化和细胞凋亡。总之，我们的研究结果表明，CF31以独特的模式靶向tRXRα，是TNFα信号从生存到死亡的有效转换者，并表明鉴定一种靶向rxr介导的调节PI3K/Akt的细胞存活途径的天然产物可能提供一种新的治疗策略来杀死癌细胞。
A truncated version of retinoid X receptor-α, tRXRα, promotes cancer cell survival by activating the PI3K/AKT pathway. However, targeting the tRXRα-mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. Pruniflorum, and the biological evaluation of its regulation of the tRXRα-mediated PI3K/AKT pathway. CF31 binds RXRα and its binding results in inhibition of RXRα transactivation. Through RXRα mutational analysis and computational studies, we show that Arg316 of RXRα, known to form salt bridges with certain RXRα ligands such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, demonstrating a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXRα. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNFα, it suppresses TNFα activation of AKT by inhibiting TNFα-induced tRXRα interaction with the p85α regulatory subunit of PI3K. CF31 inhibition of TNFα activation of AKT also results in TNFα-dependent activation of caspase-8 and apoptosis. Together, our results demonstrate that CF31 is an effective converter of TNFα signaling from survival to death by targeting tRXRα in a unique mode and suggest that identification of a natural product that targets an RXR-mediated cell survival pathway that regulates PI3K/Akt may offer a new therapeutic strategy to kill cancer cells.