CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathwayin human erythroleukemia cells
CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathwayin human erythroleukemia cells
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DOI：
10.1038/sj.onc.1209581
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发表时间：
2006-09-21
期刊：
影响因子：
8
通讯作者：
Robert-Lezenes, J.
中科院分区：
文献类型：
--
作者：
Artus, C.;Maquarre, E.;Robert-Lezenes, J.
抗 CD44 单克隆抗体 (mAb) 连接细胞表面分子 CD44 已被证明可诱导细胞分化、细胞生长抑制，在某些情况下还可诱导骨髓白血病细胞凋亡。我们在此报告，将人红白血病 HEL 细胞暴露于抗 CD44 mAb A3D8 导致细胞生长抑制，随后导致不依赖 caspase 的细胞凋亡样细胞死亡。这一过程与线粒体膜电位 (Delta Psi m) 的破坏、线粒体凋亡诱导因子 (AIF) 的释放（但不包括细胞色素 c）以及 AIF 的核转位有关。所有这些效应，包括细胞死亡、线粒体 Delta Psi m 损失和 AIF 释放，都可以通过聚（ADP-核糖）聚合酶抑制剂异喹啉预处理来阻断。通过使用小干扰 RNA 进行 AIF，还观察到了对细胞死亡的显着保护作用。此外，我们发现钙蛋白酶在细胞凋亡出现之前被激活，钙蛋白酶抑制剂或钙蛋白酶-siRNA 转染可减少 A3D8 诱导的细胞死亡，并阻止 AIF 释放。这些数据表明，CD44 连接通过红白血病 HEL 细胞中钙蛋白酶依赖性 AIF 的释放，触发了一种新型的不依赖 caspase 的细胞死亡途径。
Ligation of the cell surface molecule CD44 by anti-CD44 monoclonal antibodies (mAbs) has been shown to induce cell differentiation, cell growth inhibition and in some cases, apoptosis in myeloid leukemic cells. We report, herein, that exposure of human erythroleukemic HEL cells to the anti-CD44 mAb A3D8 resulted in cell growth inhibition followed by caspase-independent apoptosis-like cell death. This process was associated with the disruption of mitochondrial membrane potential (Delta Psi m), the mitochondrial release of apoptosis-inducing factor (AIF), but not of cytochrome c, and the nuclear translocation of AIF. All these effects including cell death, loss of mitochondrial Delta Psi m and AIF release were blocked by pretreatment with the poly(ADP-ribose) polymerase inhibitor isoquinoline. A significant protection against cell death was also observed by using small interfering RNA for AIF. Moreover, we show that calpain protease was activated before the appearance of apoptosis, and that calpain inhibitors or transfection of calpain-siRNA decrease A3D8-induced cell death, and block AIF release. These data suggest that CD44 ligation triggers a novel caspase-independent cell death pathway via calpain-dependent AIF release in erythroleukemic HEL cells.