Antagonist effect of triptolide on AKT activation by truncated retinoid X receptor-alpha.
Antagonist effect of triptolide on AKT activation by truncated retinoid X receptor-alpha.
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雷公藤甲素对截短类视黄醇 X 受体-α 激活 AKT 的拮抗作用
DOI：
10.1371/journal.pone.0035722
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zeng JZ
中科院分区：
文献类型：
--
作者：
Lu N;Liu J;Liu J;Zhang C;Jiang F;Wu H;Chen L;Zeng W;Cao X;Yan T;Wang G;Zhou H;Lin B;Yan X;Zhang XK;Zeng JZ
维甲酸X受体α（RXRα）是核受体超家族的重要成员。我们最近发现，RXRα的蛋白水解切割导致产生截短产物tRXRα，其通过激活磷脂酰肌醇-3-OH激酶（PI 3 K）/AKT途径促进癌细胞存活。然而，tRXRα介导的信号通路在癌细胞中是如何调节的仍然是难以捉摸的。我们从天然产物库中筛选出tRXRα靶向先导化合物，并在体外和动物实验中鉴定出雷公藤内酯醇（TryptyrygiumwilfordiHookF）对tRXRα介导的肿瘤细胞存活通路具有调节作用。我们的研究结果表明，雷公藤甲素强烈诱导依赖于细胞内tRXRα表达水平的癌细胞凋亡，表明tRXRα作为雷公藤甲素的重要细胞内靶点。我们发现雷公藤内酯醇选择性地诱导tRXRα降解并抑制tRXRα依赖的AKT活性，而不影响全长RXRα。有趣的是，雷公藤内酯醇的这种作用是由于其激活p38。虽然雷公藤甲素也激活Erk 1/2和MAPK通路，但雷公藤甲素对tRXRα降解和AKT活性的影响仅被p38 siRNA和p38抑制剂逆转。此外，p38抑制剂有效抑制tRXRα与p85α的相互作用，导致AKT失活。我们的研究结果证明了p38和AKT之间通过tRXRα介导的有趣的新型信号相互作用。我们的研究结果表明，雷公藤甲素靶向tRXRα强烈激活TNFα死亡信号，增强其他化疗药物的抗癌活性。我们的研究结果确定雷公藤甲素作为tRXRα依赖性生存途径的一种新的外源性调节剂，并为雷公藤甲素诱导癌细胞凋亡的机制提供了新的见解。雷公藤内酯醇是传统中药天然产物中最有前途的治疗药物之一，但其副作用令人遗憾。我们的发现将为开发用于癌症治疗的改进的雷公藤内酯醇类似物提供新的策略。
Retinoid X receptor-alpha (RXRα) is a key member of the nuclear receptor superfamily. We recently demonstrated that proteolytic cleavage of RXRα resulted in production of a truncated product, tRXRα, which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. However, how the tRXRα-mediated signaling pathway in cancer cells is regulated remains elusive. We screened a natural product library for tRXRα targeting leads and identified that triptolide, an active component isolated from traditional Chinese herb Trypterygium wilfordii Hook F, could modulate tRXRα-mediated cancer cell survival pathway in vitro and in animals. Our results reveal that triptolide strongly induces cancer cell apoptosis dependent on intracellular tRXRα expression levels, demonstrating that tRXRα serves as an important intracellular target of triptolide. We show that triptolide selectively induces tRXRα degradation and inhibits tRXRα-dependent AKT activity without affecting the full-length RXRα. Interestingly, such effects of triptolide are due to its activation of p38. Although triptolide also activates Erk1/2 and MAPK pathways, the effects of triptolide on tRXRα degradation and AKT activity are only reversed by p38 siRNA and p38 inhibitor. In addition, the p38 inhibitor potently inhibits tRXRα interaction with p85α leading to AKT inactivation. Our results demonstrate an interesting novel signaling interplay between p38 and AKT through tRXRα mediation. We finally show that targeting tRXRα by triptolide strongly activates TNFα death signaling and enhances the anticancer activity of other chemotherapies Our results identify triptolide as a new xenobiotic regulator of the tRXRα-dependent survival pathway and provide new insight into the mechanism by which triptolide acts to induce apoptosis of cancer cells. Triptolide represents one of the most promising therapeutic leads of natural products of traditional Chinese medicine with unfortunate side-effects. Our findings will offer new strategies to develop improved triptolide analogs for cancer therapy.
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影响因子：
11.2
作者：
Liu J;Zhou W;Li SS;Sun Z;Lin B;Lang YY;He JY;Cao X;Yan T;Wang L;Lu J;Han YH;Cao Y;Zhang XK;Zeng JZ
通讯作者：
Zeng JZ
影响因子：
6.2
作者：
Fidler, JM;Ku, GY;Chen, ZQ
通讯作者：
Chen, ZQ
影响因子：
20.3
作者：
Carter, Bing Z.;Mak, Duncan H.;Andreeff, Michael
通讯作者：
Andreeff, Michael
影响因子：
4.8
作者：
Lee, KY;Chang, WT;Rosen, GD
通讯作者：
Rosen, GD
影响因子：
2.6
作者：
Chen, BJ
通讯作者：
Chen, BJ