Quercetin induces tumor-selective apoptosis through downregulation of Mcl-1 and activation of Bax.
Quercetin induces tumor-selective apoptosis through downregulation of Mcl-1 and activation of Bax.
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DOI：
10.1158/1078-0432.ccr-10-1565
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发表时间：
2010-12-01
期刊：
影响因子：
--
通讯作者：
Shi X
中科院分区：
文献类型：
--
作者：
Cheng S;Gao N;Zhang Z;Chen G;Budhraja A;Ke Z;Son YO;Wang X;Luo J;Shi X
探讨槲皮素对U937移植瘤的体内抗肿瘤作用及Mcl-1和Bax在槲皮素诱导人白血病细胞凋亡中的作用。用槲皮素处理白血病细胞，之后评估凋亡、Mcl-1表达和Bax活化和易位。在白血病细胞异种移植物中研究了槲皮素的功效以及Mcl-1表达和Bax活化。槲皮素的管理引起显着的凋亡转化和原代白血病细胞，但不是在正常血液外周血单核细胞。槲皮素诱导的细胞凋亡伴随着Mcl-1的下调和Bax构象的改变以及线粒体转位，从而触发细胞色素c的释放。通过siRNA敲低Bax逆转槲皮素诱导的细胞凋亡。Bax基因敲除可抑制caspase的激活和细胞凋亡。Mcl-1的异位表达减弱了槲皮素介导的Bax激活、易位和细胞死亡。相反，通过siRNA中断Mcl-1增强Bax激活和易位，以及槲皮素诱导的致死性。然而，Bax的缺失对槲皮素介导的Mcl-1下调没有影响。此外，在U937异种移植物中，槲皮素的体内给药减弱了肿瘤生长。槲皮素处理组肿瘤切片中TUNEL阳性凋亡细胞数较对照组增多。在异种移植物中观察到Mcl-1下调和Bax活化。这些数据表明，槲皮素可能是有用的治疗白血病，通过优先诱导白血病细胞凋亡相对于正常造血细胞，通过一个过程，涉及Mcl-1下调，这反过来又加强Bax激活和线粒体易位，最终在凋亡。
To investigate the in vivo antitumor efficacy of querctin in U937 xenografts and the functional role of Mcl-1 and Bax in quercetin-induced apoptosis in human leukemia cells. Leukemia cells were treated with quercetin, after which apoptosis, Mcl-1 expression, and Bax activation and translocation were evaluated. The efficacy of quercein, as well as Mcl-1 expression and Bax activation were investigated in xenografts of leukemia cells. Administration of quercetin caused pronounced apoptosis in both transformed and primary leukemia cells, but not in normal blood peripheral mononuclear cells. Quercetin-induced apoptosis was accompanied by Mcl-1 down-regulation and Bax conformational change and mitochondrial translocation which triggered cytochrome c release. Knockdown of Bax by siRNA reversed querctin-induced apoptosis. Knockout of Bax abrogated the activation of caspase and apoptosis. Ectopic expression of Mcl-1 attenuated quercetin-mediated Bax activation, translocation and cell death. Conversely, interruption of Mcl-1 by siRNA enhanced Bax activation and translocation, as well as lethality induced by quercetin. However, the absence of Bax had no effect on quercetin-mediated Mcl-1 down-regulation. Furthermore, in vivo administration of quercetin attenuated tumor growth in U937 xenografts. The TUNEL positive apoptotic cells in tumor sections increased in quercetin-treated mice as compared with controls. Mcl-1 down-regulation and Bax activation were observed in xenografts. These data suggest that quercetin may be useful for the treatment of leukemia by preferentially inducing apoptosis in leukemia versus normal hematopoietic cells, through a process involving Mcl-1 down-regulation, which in turn potentiates Bax activation and mitochondrial translocation, culminating in apoptosis.