Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1
Induction of apoptosis by thymoquinone in lymphoblastic leukemia Jurkat cells is mediated by a p73-dependent pathway which targets the epigenetic integrator UHRF1
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DOI：
10.1016/j.bcp.2009.12.015
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发表时间：
2010-05-01
影响因子：
5.8
通讯作者：
Fuhrmann, Guy
中科院分区：
文献类型：
--
作者：
Alhosin, Mahmoud;Abusnina, Abdurazzag;Fuhrmann, Guy
涉及p53相关p73基因的补救抗肿瘤途径尚未完全表征。因此，我们试图通过关注对细胞周期进程至关重要的抗凋亡和表观遗传整合子UHRF 1，来确定参与p73依赖性促凋亡途径激活的上游和下游事件。为此，我们分析了已知的抗肿瘤药物，百里醌（TQ），对p53缺陷型急性淋巴细胞白血病（ALL）Jurkat细胞系的影响。结果表明，TQ能抑制Jurkat细胞增殖，并诱导细胞周期阻滞，且呈剂量依赖性。此外，TQ处理触发程序性细胞死亡、活性氧（ROS）的产生和线粒体膜电位（Δ Psi m）的改变。经亚二倍体G 0/G1细胞的存在证实，TQ诱导的细胞凋亡与p73的快速和急剧的再表达以及caspase-3裂解亚基水平的剂量依赖性变化相关。这些修饰伴随着UHRF 1及其两个主要伙伴，即DNMT 1和HDAC 1的显著下调，它们都参与了表观遗传密码调控。敲低p73表达可恢复UHRF 1表达，重新激活细胞周期进程并抑制TQ诱导的细胞凋亡。总之，我们的研究结果表明，TQ介导其对ALL p53突变细胞的生长抑制作用，通过激活p73依赖性线粒体和细胞周期检查点信号通路，随后靶向UHRF 1。(C)2009 Elsevier Inc. All rights reserved.
The salvage anti-tumoral pathway which implicates the p53-related p73 gene is not yet fully characterized. We therefore attempted to identify the up- and down-stream events involved in the activation of the p73-dependent pro-apoptotic pathway, by focusing on the anti-apoptotic and epigenetic integrator UHRF1 which is essential for cell cycle progression. For this purpose, we analyzed the effects of a known anti-neoplastic drug, thymoquinone (TQ), on the p53-deficient acute lymphoblastic leukemia (ALL) Jurkat cell line. Our results showed that TQ inhibits the proliferation of Jurkat cells and induces G I cell cycle arrest in a dose-dependent manner. Moreover, TQ treatment triggers programmed cell death, production of reactive oxygen species (ROS) and alteration of the mitochondrial membrane potential (Delta Psi m). TQ-induced apoptosis, confirmed by the presence of hypodiploid G0/G1 cells, is associated with a rapid and sharp re-expression of p73 and dose-dependent changes of the levels of caspase-3 cleaved subunits. These modifications are accompanied by a dramatic down-regulation of UHRF1 and two of its main partners, namely DNMT1 and HDAC1, which are all involved in the epigenetic code regulation. Knockdown of p73 expression restores UHRF1 expression, reactivates cell cycle progression and inhibits TQ-induced apoptosis. Altogether our results showed that TQ mediates its growth inhibitory effects on ALL p53-mutated cells via the activation of a p73-dependent mitochondrial and cell cycle checkpoint signaling pathway which subsequently targets UHRF1. (C) 2009 Elsevier Inc. All rights reserved.