Comparison of apoptosis in wild-type and fas-resistant cells: Chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions
Comparison of apoptosis in wild-type and fas-resistant cells: Chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions
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DOI：
10.1182/blood.v90.3.935.935_935_943
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发表时间：
1997-08-01
期刊：
影响因子：
20.3
通讯作者：
Kaufmann, SH
中科院分区：
文献类型：
--
作者：
Eischen, CM;Kottke, TJ;Kaufmann, SH
Fas/Fas配体（FasL）途径广泛参与淋巴细胞和非淋巴细胞的凋亡，近来推测许多化疗药物也通过激活Fas/FasL途径诱导细胞死亡。在本研究中，我们比较了Jurkat人T细胞白血病细胞系中抗Fas或化疗药物诱导的凋亡途径。免疫印迹显示，用抗Fas或拓扑异构酶II导向剂依托泊苷处理野生型Jurkat细胞导致半胱氨酸依赖性谷氨酸导向蛋白酶caspase-3和caspase-7的前体的蛋白水解裂解，以及caspase底物聚（ADP-核糖）聚合酶（PARP）和核纤层蛋白B-1的降解。同样，用N-（N-α-苄氧基羰基谷氨酰基-N-ε-生物素基赖氨酰基）天冬氨酸[（2，6-二甲基-苯甲酰基）氧基]甲基酮[Z-EK（bio）D-amok]进行亲和标记在每次处理后标记相同的五种活性半胱天冬酶种类，表明相同的下游凋亡途径已被抗Fas和依托泊苷激活。用抑制Fas介导的细胞死亡的抗体ZB 4治疗，未能阻断依托泊苷诱导的细胞凋亡，提高了依托泊苷不通过Fas/FasL相互作用启动细胞凋亡的可能性。为了进一步探讨Fas和化疗诱导的细胞凋亡之间的关系，Fas耐药的Jurkat细胞用各种化疗药物处理。多个独立衍生的Fas耐药Jurkat细胞系在用依托泊苷、多柔比星、拓扑替康、顺铂、甲氨蝶呤、星形孢菌素或γ-照射处理后经历了与Fas敏感性亲本细胞难以区分的凋亡。这些结果表明，即使Fas和化疗诱导的途径会聚在共同的下游凋亡效应分子上，但顺铂治疗通过Fas非依赖性途径诱导细胞凋亡。(C)1997年，美国血液学会。
The Fas/Fas ligand (FasL) pathway is widely involved in apoptotic cell death in lymphoid and nonlymphoid cells, It has recently been postulated that many chemotherapeutic agents also induce cell death by activating the Fas/FasL pathway. In the present study we compared apoptotic pathways induced by anti-Fas or chemotherapeutic agents in the Jurkat human T-cell leukemia line. Immunoblotting showed that treatment of wild-type Jurkat cells with anti-fas or the topoisomerase II-directed agent etoposide resulted in proteolytic cleavage of precursors for the cysteine-dependent aspartate-directed proteases caspase-3 and caspase-7 and degradation of the caspase substrates poly(ADP-ribose) polymerase (PARP) and lamin B-1. Likewise, affinity labeling with N-(N-alpha-benzyloxycarbonylglutamyl-N-epsilon-biotinyllysyl)aspartic acid [(2,6-dimethyl-benzoyl)oxy]methyl ketone [Z-EK (bio)D-amok] labeled the same five active caspase species after each treatment, suggesting that the same downstream apoptotic pathways have been activated by anti-Fas and etoposide. Treatment with ZB4, an antibody that inhibits Fas-mediated cell death, failed to block etoposide-induced apoptosis, raising the possibility that etoposide does not initiate apoptosis through Fas/FasL interactions. To further explore the relationship between Fas- and chemotherapy-induced apoptosis, Fas-resistant Jurkat cells were treated with various chemotherapeutic agents. Multiple independently derived Fas-resistant Jurkat lines underwent apoptosis that was indistinguishable from that of the Fas-sensitive parental cells after treatment with etoposide, doxorubicin, topotecan, cisplatin, methotrexate, staurosporine, or gamma-irradiation. These results indicate that antineoplastic treatments induce apoptosis through a Fas-independent pathway even though Fas- and chemotherapy-induced pathways converge on common downstream apoptotic effector molecules. (C) 1997 by The American Society of Hematology.