Downregulation of Mcl-1 through GSK-3β activation contributes to arsenic trioxide-induced apoptosis in acute myeloid leukemia cells.
Downregulation of Mcl-1 through GSK-3β activation contributes to arsenic trioxide-induced apoptosis in acute myeloid leukemia cells.
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DOI：
10.1038/leu.2012.180
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发表时间：
2013-02
期刊：
影响因子：
11.4
通讯作者：
Jing, Y.
中科院分区：
文献类型：
--
作者：
Wang, R.;Xia, L.;Gabrilove, J.;Waxman, S.;Jing, Y.
三氧化二砷（ATO）在急性早幼粒细胞白血病（APL）患者中诱导疾病缓解，但在非APL急性髓系白血病（AML）患者中不起作用。治疗浓度（1-2 μM）的ATO通过线粒体途径诱导APL细胞NB4凋亡，而非APL细胞HL-60凋亡。研究抗凋亡蛋白Mcl-1在ato诱导的细胞凋亡中的作用。ATO通过蛋白酶体降解处理后，NB4细胞中Mcl-1水平降低，HL-60细胞中则没有。GSK3β抑制剂SB216763和siRNA均可阻断ato诱导的Mcl-1减少，并减弱ato诱导的NB4细胞凋亡。沉默Mcl-1使HL-60细胞对ato诱导的凋亡敏感。ERK和AKT抑制剂均可降低Mcl-1水平，增强ato诱导的HL-60细胞凋亡。Sorafenib是一种Raf抑制剂，通过抑制GSK3β的磷酸化，降低Mcl-1水平，降低HL-60细胞内谷胱甘肽水平，从而激活GSK3β。索拉非尼加ATO增强HL-60细胞和原代AML细胞的ROS生成和凋亡诱导。这些结果表明，ATO通过激活APL细胞中的GSK3β诱导Mcl-1降解，并为利用ATO联合索拉非尼治疗非APL AML患者提供了理论依据。
Arsenic trioxide (ATO) induces disease remission in acute promyelocytic leukemia (APL) patients, but not in non-APL acute myeloid leukemia (AML) patients. ATO at therapeutic concentrations (1-2 μM) induce APL NB4, but not non-APL HL-60, cells to undergo apoptosis through the mitochondrial pathway. The role of antiapoptotic protein Mcl-1 in ATO-induced apoptosis was determined. The levels of Mcl-1 were decreased in NB4, but not in HL-60, cells after ATO treatment through proteasomal degradation. Both GSK3β inhibitor SB216763 and siRNA blocked ATO-induced Mcl-1 reduction as well as attenuated ATO-induced apoptosis in NB4 cells. Silencing Mcl-1 sensitized HL-60 cells to ATO-induced apoptosis. Both ERK and AKT inhibitors decreased Mcl-1 levels and enhanced ATO-induced apoptosis in HL-60 cells. Sorafenib, a Raf inhibitor, activated GSK3β by inhibiting its phosphorylation, decreased Mcl-1 levels, and decreased intracellular glutathione levels in HL-60 cells. Sorafenib plus ATO augmented ROS production and apoptosis induction in HL-60 cells and in primary AML cells. These results indicate that ATO induces Mcl-1 degradation through activation of GSK3β in APL cells and provide a rationale for utilizing ATO in combination with sorafenib for the treatment of non-APL AML patients.
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影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
通讯作者：
Wei, Wenyi
影响因子：
11.2
作者：
Chen, Duo;Chan, Rosemarie;Jing, Yongkui
通讯作者：
Jing, Yongkui
影响因子：
5.3
作者：
Ding, Qingqing;He, Xianghuo;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie
DOI：
10.1073/pnas.0306687101
发表时间：
2004-03-30
影响因子：
11.1
作者：
Chou, WC;Jie, CF;Dang, CV
通讯作者：
Dang, CV
影响因子：
11.4
作者：
Huber, S.;Oelsner, M.;Ringshausen, I.
通讯作者：
Ringshausen, I.