Piperlongumine is a novel nuclear export inhibitor with potent anticancer activity
Piperlongumine is a novel nuclear export inhibitor with potent anticancer activity
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Piperlongumine 是一种新型核输出抑制剂，具有有效的抗癌活性。
DOI：
10.1016/j.cbi.2015.05.016
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发表时间：
2015-07-25
影响因子：
5.1
通讯作者：
Xu, Kailin
中科院分区：
文献类型：
--
作者：
Niu, Mingshan;Xu, Xiaoyu;Xu, Kailin
马洛古明是一种天然化合物，最近被鉴定为在体外和体内对肿瘤细胞具有选择性毒性。然而，其抗肿瘤作用的分子机制仍不清楚。在这份报告中，我们描述了另一种新的机制，piperlongumine介导其抗肿瘤作用。我们发现，piperlongumine是一种新的核输出抑制剂。结果表明，马唐明可诱导肿瘤抑制蛋白质的核滞留，并抑制CRM1与这些蛋白质的相互作用。该蛋白能与CRM1的保守Cys528结合，但不能与Cys528突变肽结合。更重要的是，表达突变CRM1（C528S）的癌细胞对piperlongumine具有抗性，证明了通过与CRM1的Cys528直接相互作用的核输出抑制。piperlongumine对核输出的抑制作用可能是其治疗癌症的原因。我们的研究结果为开发新型CRM1抑制剂提供了一个很好的起点。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Piperlongumine is a natural compound recently identified to be toxic selectively to tumor cells in vitro and in vivo. However, the molecular mechanism underlying its anti-tumor action still remains unclear. In this report, we describe another novel mechanism by which piperlongumine mediates its anti-tumor effects. We found that piperlongumine is a novel nuclear export inhibitor. Piperlongumine could induce nuclear retention of tumor suppressor proteins and inhibit the interactions between CRM1 and these proteins. Piperlongumine could directly bind to the conserved Cys528 of CRM1 but not to a Cys528 mutant peptide. More importantly, cancer cells expressing mutant CRM1 (C528S) are resistant to piperlongumine, demonstrating the nuclear export inhibition via direct interaction with Cys528 of CRM1. The inhibition of nuclear export by piperlongumine may account for its therapeutic properties in cancer diseases. Our findings provide a good starting point for development of novel CRM1 inhibitors. (C) 2015 Elsevier Ireland Ltd. All rights reserved.