Inhibition of miR-17 and miR-20a by Oridonin Triggers Apoptosis and Reverses Chemoresistance by Derepressing BIM-S
Inhibition of miR-17 and miR-20a by Oridonin Triggers Apoptosis and Reverses Chemoresistance by Derepressing BIM-S
复制标题
冬凌草甲素抑制 miR-17 和 miR-20a 可触发细胞凋亡并通过去抑制 BIM-S 逆转化疗耐药性
DOI：
10.1158/0008-5472.can-13-1748
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发表时间：
2014-08-16
期刊：
影响因子：
11.2
通讯作者：
Qu, Lianghu
中科院分区：
文献类型：
--
作者：
Weng, Hengyou;Huang, Huilin;Qu, Lianghu
癌细胞的化疗耐药部分是通过获得对凋亡的抵抗而产生的。研究发现，耐受化疗诱导的白血病细胞对冬凌草甲素敏感，冬凌草甲素是一种具有强大抗癌活性的天然药物。为了探讨冬凌草甲素逆转化疗耐药的作用机制，我们比较了冬凌草甲素与抗白血病药物Ara-C和VP-16对人白血病细胞的反应。与HL60细胞相比，K562和K562/ADR细胞对Ara-C和VP-16诱导的细胞凋亡表现出抵抗，而对冬凌草甲素敏感。机制研究表明冬凌草甲素通过下调miR-17和miR-20a的表达上调BIM-S，导致线粒体依赖性的细胞凋亡。相反，Ara-C和VP-16都不能降低miR-17和miR-20a的表达，也不能触发BIM-S介导的细胞凋亡。值得注意的是，用microRNA(miRNA；miR)抑制剂或冬凌草甲素抑制miR-17或miR-20a的表达，可以恢复K562细胞对VP-16的敏感性。冬凌草甲素和VP-16在培养细胞和小鼠肿瘤移植瘤实验中有协同作用。抑制miR-17或miR-20a也能增强冬凌草甲素的促凋亡活性。综上所述，我们的结果确定了冬凌草甲素抗癌作用的miRNA依赖机制，并为其与化疗药物联合治疗化疗耐药白血病细胞提供了理论基础。(C)2014年AACR。
Cancer cell chemoresistance arises in part through the acquisition of apoptotic resistance. Leukemia cells resistant to chemotherapy-induced apoptosis have been found to be sensitive to oridonin, a natural agent with potent anticancer activity. To investigate its mechanisms of action in reversing chemoresistance, we compared the response of human leukemia cells with oridonin and the antileukemia drugs Ara-C and VP-16. Compared with HL60 cells, K562 and K562/ADR cells displayed resistance to apoptosis stimulated by Ara-C and VP-16 but sensitivity to oridonin. Mechanistic investigations revealed that oridonin upregulated BIM-S by diminishing the expression of miR-17 and miR-20a, leading to mitochondria-dependent apoptosis. In contrast, neither Ara-C nor VP-16 could reduce miR-17 and miR-20a expression or could trigger BIM-S-mediated apoptosis. Notably, silencing miR-17 or miR-20a expression by treatment with microRNA (miRNA; miR) inhibitors or oridonin restored sensitivity of K562 cells to VP-16. Synergistic effects of oridonin and VP-16 were documented in cultured cells as well as mouse tumor xenograft assays. Inhibiting miR-17 or miR-20a also augmented the proapoptotic activity of oridonin. Taken together, our results identify a miRNA-dependent mechanism underlying the anticancer effect of oridonin and provide a rationale for its combination with chemotherapy drugs in addressing chemoresistant leukemia cells. (C)2014 AACR.