2-methoxyestradiol-induced apoptosis in human leukemia cells proceeds through a reactive oxygen species and Akt-dependent process
2-methoxyestradiol-induced apoptosis in human leukemia cells proceeds through a reactive oxygen species and Akt-dependent process
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DOI：
10.1038/sj.onc.1208530
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发表时间：
2005-05-26
期刊：
影响因子：
8
通讯作者：
Grant, S
中科院分区：
文献类型：
--
作者：
Gao, N;Rahmani, M;Grant, S
在人白血病细胞（U937和Jurkat）中，研究了2-甲氧基雌二醇（2ME）诱导的细胞凋亡与线粒体损伤、氧化损伤和信号通路扰动的关系。2ME以剂量依赖的方式诱导这些细胞凋亡，与线粒体蛋白（细胞色素c， AIF）的释放、活性氧（ROS）的产生、Mcl-1和XIAP的下调以及Akt的失活（去磷酸化）伴随JNK的激活有关。在这些细胞中，由组成性活性的多肌化Akt构建体强制激活Akt可阻止2me介导的线粒体损伤、XIAP和Mcl-1下调、JNK激活和凋亡，但不能阻止ROS的产生。相反，磷脂酰肌醇3-激酶（PI3K）抑制剂LY294002增强了2ME的致病性。此外，在U937细胞中，过氧化氢清除剂过氧化氢酶和超氧化物歧化酶（SOD）模拟物TBAP阻断了这些事件以及Akt的失活。药理学或遗传学（如siRNA）阻断JNK通路意味着2me诱导的线粒体损伤、XIAP和Mcl-1下调和细胞凋亡减弱。综上所述，这些发现提示了2me诱导人白血病细胞凋亡的分层模型，其中2me诱导的氧化损伤是导致Akt失活的主要事件，进而导致JNK活化，最终导致XIAP和Mcl-1下调、线粒体损伤和细胞凋亡。他们还表明，在人类白血病细胞中，Akt通路在介导2ME诱导的氧化应激反应中起着关键作用。
The effects of 2-Methoxyestradiol (2ME)-induced apoptosis was examined in human leukemia cells (U937 and Jurkat) in relation to mitochondrial injury, oxidative damage, and perturbations in signaling pathways. 2ME induced apoptosis in these cells in a dose-dependent manner associated with release of mitochondrial proteins ( cytochrome c, AIF), generation of reactive oxygen species (ROS), downregulation of Mcl-1 and XIAP, and inactivation ( dephosphorylation) of Akt accompanied by activation of JNK. In these cells, enforced activation of Akt by a constitutively active myristolated Akt construct prevented 2ME-mediated mitochondrial injury, XIAP and Mcl-1 downregulation, JNK activation, and apoptosis, but not ROS generation. Conversely, 2ME lethality was potentiated by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Furthermore, in U937 cells, the hydrogen peroxide scavenger catalase and a superoxide dismutase ( SOD) mimetic, TBAP, blocked these events, as well as Akt inactivation. Interruption of the JNK pathway by pharmacologic or genetic ( e. g. siRNA) means attenuated 2ME-induced mitochondrial injury, XIAP and Mcl-1 downregulation, and apoptosis. Collectively, these findings suggest a hierarchical model of 2ME-related apoptosis induction in human leukemia cells in which 2ME-induced oxidative injury represents a primary event resulting in Akt inactivation, leading, in turn, to JNK activation, and culminating in XIAP and Mcl-1 downregulation, mitochondrial injury, and apoptosis. They also suggest that in human leukemia cells, the Akt pathway plays a critical role in mediating the response to oxidative stress induced by 2ME.