Curcumin promotes apoptosis by activating the p53-miR-192-5p/215-XIAP pathway in non-small cell lung cancer
Curcumin promotes apoptosis by activating the p53-miR-192-5p/215-XIAP pathway in non-small cell lung cancer
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姜黄素通过激活非小细胞肺癌中的 p53-miR-192-5p/215-XIAP 通路促进细胞凋亡。
DOI：
10.1016/j.canlet.2014.11.028
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发表时间：
2015-02-01
期刊：
影响因子：
9.7
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Ye, Mingxiang;Zhang, Jin;Zhang, Jian
几十年来，姜黄素作为抗癌药物引起了越来越多的兴趣。作用机制涉及多种癌症相关信号通路。最近的研究强调姜黄素对癌症中的miRNA具有表观遗传调节作用。在本研究中，我们证明了姜黄素在体外和体内的促凋亡作用。miRNA微阵列和qPCR显示miR-192- 5 p和miR-215是姜黄素处理后H460和A427细胞中最具响应性的miRNA。功能研究显示miR-192- 5 p/215是非小细胞肺癌的假定肿瘤抑制因子。姜黄素也促进miR-192- 5 p/215在A549细胞（p53野生型）中的表达，但在H1299细胞（p53-null）中不促进。四环素诱导表达系统对p53的条件性敲低显著消除了姜黄素诱导的p53野生型H460、A427和A549细胞中miR-192- 5 p/215的上调。相反，在p53缺失的H1299细胞中，外源野生型而非R273 H突变型p53的异位表达使得miR 192 - 5 p/215能够对姜黄素处理产生应答。姜黄素的促凋亡作用也依赖于miR-192- 5 p/215的诱导，拮抗miR-192- 5 p/215的表达减弱了姜黄素在H460、A427和A549细胞中诱导的凋亡，但在H1299细胞中没有。X-linked inhibitor of apoptosis（XIAP）是miR-192- 5 p/215的一个新的转录靶点。总之，这项研究强调了姜黄素的促凋亡作用依赖于miR-192- 5 p/215诱导，而p53-miR-192- 5 p/215-XIAP通路是非小细胞肺癌的重要治疗靶点。(c)2014爱思唯尔爱尔兰有限公司版权所有。
Curcumin has attracted increasing interest as an anti-cancer drug for decades. The mechanisms of action involve multiple cancer-related signaling pathways. Recent studies highlighted curcumin has epigenetic regulatory effects on miRNA in cancers. In the present study, we demonstrated the proapoptotic effects of curcumin in vitro and in vivo. miRNA microarray and qPCR indicated that miR-192-5p and miR-215 were the most responsive miRNAs upon curcumin treatment in H460 and A427 cells. Functional studies showed miR-192-5p/215 were putative tumor suppressors in non-small cell lung cancer. Curcumin also promoted miR-192-5p/215 expressions in A549 cells (p53 wild type) but not in H1299 cells (p53-null). Conditional knockdown of p53 by tetracycline inducible expression system significantly abrogated curcumin-induced miR-192-5p/215 upregulation in the p53 wild-type H460, A427 and A549 cells. Conversely, ectopic expression of exogenous wild-type but not R273H mutant p53 in the p53-null H1299 cells enabled miR192-5p/215 response to curcumin treatment. The proapoptotic effects of curcumin also depended on miR-192-5p/215 induction, and antagonizing miR-192-5p/215 expression attenuated curcumin-induced apoptosis in H460, A427 and A549 cells, but not in H1299 cells. Finally, X-linked inhibitor of apoptosis (XIAP) is proved to be a novel transcriptional target of miR-192-5p/215. Taken together, this study highlights that the proapoptotic effects of curcumin depend on miR-192-5p/215 induction and the p53-miR-192-5p/215-XIAP pathway is an important therapeutic target for non-small cell lung cancer. (c) 2014 Elsevier Ireland Ltd. All rights reserved.