Processing/activation of caspases, -3 and -7 and -8 but not caspase-2, in the induction of apoptosis in B-chronic lymphocytic leukemia cells
Processing/activation of caspases, -3 and -7 and -8 but not caspase-2, in the induction of apoptosis in B-chronic lymphocytic leukemia cells
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DOI：
10.1038/sj.leu.2401153
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发表时间：
1998-10-01
期刊：
影响因子：
11.4
通讯作者：
Cohen, GM
中科院分区：
文献类型：
--
作者：
King, D;Pringle, JH;Cohen, GM
苯丁酸氮芥和泼尼松龙是治疗慢性淋巴细胞白血病（CLL）的两种常用药物，可诱导CLL细胞凋亡。我们已经研究了参与这种凋亡性细胞死亡的半胱天冬酶，其切割关键的细胞底物，从而作为凋亡过程的执行者。诱导自发的或苯丁酸氮芥/泼尼松龙诱导的新鲜分离的B-CLL细胞凋亡的培养导致激活的'效应'半胱天冬酶，-3和-7，但一般不半胱天冬酶-2。半胱天冬酶-3和-7的激活伴随着DNA修复酶聚（ADP-核糖）聚合酶的蛋白水解。细胞凋亡的诱导也伴随着caspase-8的处理，其程度因患者而异。细胞可渗透的caspase抑制剂苄氧羰基-Val-Ala-Asp（OMe）氟甲基酮（Z-VAD. fetoxin）可抑制所有caspase的凋亡诱导和加工。我们的研究结果表明，在CLL细胞凋亡的执行阶段，半胱天冬酶的激活和加工的关键作用。CLL细胞的凋亡导致部分但不是全部caspase的选择性激活。我们的研究结果表明，在慢性淋巴细胞白血病中观察到的细胞凋亡失调可能是由于信号转导导致的半胱天冬酶的激活，而不是一个删除的前半胱天冬酶。CLL细胞中高水平的半胱天冬酶-8结合低水平的CD 95受体可能为治疗CLL提供新的治疗机会。
Chlorambucil and prednisolone, two commonly used drugs in the treatment of chronic lymphocytic leukemia (CLL), induce apoptosis in CLL cells. We have investigated the involvement in this apoptotic cell death of caspases, which cleave critical cellular substrates thereby acting as the executioners of the apoptotic process. Induction of spontaneous or chlorambucil/prednisolone-induced apoptosis of freshly isolated B-CLL cells in culture resulted in the activation of the 'effector' caspases, -3 and -7, but generally not of caspase-2. Activation of caspases-3 and -7 was accompanied by the proteolysis of the DNA repair enzyme, poly (ADP-ribose) polymerase. Induction of apoptosis was also accompanied by the processing of caspase-8, the extent of which varied between patients. Induction of apoptosis and processing of all the caspases was inhibited by the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.fmk). Our results demonstrate a key role for the activation and processing of caspases in the execution phase of apoptosis in CLL cells. Apoptosis of CLL cells resulted in the selective activation of some but not all caspases. Our results suggest that the dysregulation of apoptosis observed in CLL may be due to the signalling leading to the activation of caspases rather than a deletion of pro-caspases. High levels of caspase-8 in CLL cells in conjunction with low levels of CD95 receptor may offer new therapeutic opportunities for the treatment of CLL.