Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa
Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa
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DOI：
10.1038/sj.leu.2404760
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发表时间：
2007-08-01
期刊：
影响因子：
11.4
通讯作者：
Cohen, G. M.
中科院分区：
文献类型：
--
作者：
Inoue, S.;Riley, J.;Cohen, G. M.
最近进入早期临床试验的几种组蛋白去乙酰化酶抑制剂（HDACi）部分通过诱导细胞凋亡发挥其抗癌活性，尽管这种诱导的精确机制尚不清楚。在慢性淋巴细胞白血病（CLL）患者和不同白血病细胞系的原代细胞中，由结构多样的HDACi诱导的凋亡由Bcl-2调节的内在途径介导，并证明需要从头蛋白质合成。一个显着的时间依赖性诱导的促凋亡BH 3-唯一的蛋白质，Bim，Noxa和BMF观察到，这之前的诱导细胞凋亡。Bim和Noxa在HDACi介导的细胞凋亡中起关键作用，这是基于我们的发现，Bim和Noxa的siRNA而不是Bmf在很大程度上阻止了HDACi诱导的线粒体膜电位、半胱天冬酶加工和磷脂酰丝氨酸外化的损失。在CLL细胞和肿瘤细胞系中，HDACi诱导的Noxa广泛结合于Mcl-1，Mcl-1是CLL细胞中存在的主要抗凋亡Bcl-2家族成员。我们的数据强烈表明HDACi主要通过Bim和Noxa的增加使抗凋亡Bcl-2家族成员失活来诱导凋亡，并强调这些增加是CLL/淋巴瘤治疗的潜在临床靶点。
Several histone deacetylase inhibitors (HDACi), which have recently entered early clinical trials, exert their anticancer activity in part through the induction of apoptosis although the precise mechanism of this induction is not known. Induction of apoptosis by structurally diverse HDACi in primary cells from patients with chronic lymphocytic leukemia (CLL) and different leukemic cell lines was mediated by the Bcl-2 regulated intrinsic pathway and demonstrated a requirement for de novo protein synthesis. A marked time-dependent induction of the proapoptotic BH3-only proteins, Bim, Noxa and Bmf was observed, which preceded the induction of apoptosis. A key role for both Bim and Noxa was proposed in HDACi-mediated apoptosis based on our findings that siRNA for Bim and Noxa but not Bmf largely prevented the HDACi-induced loss in mitochondrial membrane potential, caspase processing and phosphatidylserine externalization. Noxa, induced by HDACi, in CLL cells and tumor cell lines, bound extensively to Mcl-1, a major anti-apoptotic Bcl-2 family member present in CLL cells. Our data strongly suggests that HDACi induce apoptosis primarily through inactivation of anti-apoptotic Bcl-2 family members by increases in Bim and Noxa and highlights these increases as a potential clinical target for CLL/lymphoma therapy.