Bcl-2 overexpression prevents daunorubicin-induced apoptosis through inhibition of XIAP and Akt degradation
Bcl-2 overexpression prevents daunorubicin-induced apoptosis through inhibition of XIAP and Akt degradation
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DOI：
10.1016/s0006-2952(03)00545-8
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发表时间：
2003-11-01
影响因子：
5.8
通讯作者：
Kwon, TK
中科院分区：
文献类型：
--
作者：
Kim, YH;Park, JW;Kwon, TK
柔红霉素（DNR）通过激活中性鞘磷脂酶和神经酰胺的产生诱导人髓性白血病细胞凋亡。在本研究中，我们确定了抗凋亡蛋白Bcl-2对caspase-3激活，磷脂酶C-γ 1（PLC-γ 1）降解和细胞色素C释放在柔红霉素诱导的细胞凋亡的影响。用3 μ M DNR处理12小时，在U937细胞中产生凋亡和DNA片段化的形态学特征，这与caspase-3激活和PLC-γ 1降解有关。细胞凋亡的诱导还伴随着细胞色素c的释放、X连锁凋亡蛋白抑制剂（XIAP）的下调和Akt的失活，这被泛半胱天冬酶抑制剂z-VAD-favor阻断。在Bcl-2过表达的U937/Bcl-2细胞中，柔红霉素诱导的caspase-3活化、PLC-γ 1降解和凋亡显著减弱。Bcl-2的异位表达似乎通过干扰XIAP和Akt降解的抑制来抑制DNR诱导的细胞凋亡。(C)2003年爱思唯尔公司All rights reserved.
Daunorubicin (DNR) induces apoptosis in the human myeloid leukemia cells by activation of neutral sphingomyelin ease and ceramide production. In the present study, we determined the effect of the antiapoptosis protein Bcl-2 on caspase-3 activation, phospholipase C-gamma1 (PLC-gamma1) degradation and cytochrome c release during the DNR-induced apoptosis. Treatment with 3 muM DNR for 12 hr produced morphological features of apoptosis and DNA fragmentation in U937 cells, which was associated with caspase-3 activation and PLC-gamma1 degradation. Induction of apoptosis was also accompanied by release of cytochrome c, down-regulation of X-linked inhibitor of apoptosis protein (XIAP), and inactivation of Akt, which was blocked by the pan-caspase inhibitor z-VAD-fmk. DNR-induced caspase-3 activation, PLC-gamma1 degradation and apoptosis were significantly attenuated in Bcl-2 overexpressing U937/Bcl-2 cells. Ectopic expression of Bcl-2 appeared to inhibit DNR-induced apoptosis by interfering with inhibition of XIAP and Akt degradation. (C) 2003 Elsevier Inc. All rights reserved.