Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells
Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells
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DOI：
10.1038/sj.leu.2400827
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发表时间：
1997-11-01
期刊：
影响因子：
11.4
通讯作者：
Debatin, KM
中科院分区：
文献类型：
--
作者：
Friesen, C;Fulda, S;Debatin, KM
肿瘤细胞对化疗的敏感性和抗性的分子机制仅部分了解。在化学敏感性白血病和实体瘤中，抗癌药物已显示出诱导细胞凋亡。我们以前确定了CD 95（APO-1/Fas）受体/CD 95配体（CD 95/CD 95-L）系统的激活是药物诱导细胞凋亡的关键机制。在这里，我们表明，治疗浓度的阿霉素，甲氨蝶呤和阿糖胞苷也诱导凋亡，通过激活的CD 95系统在体内的原代白血病细胞，CD 95耐药和阿霉素耐药白血病和神经母细胞瘤细胞显示交叉耐药诱导细胞死亡。在耐药和CD 95耐药细胞系中发现CD 95表达下调。此外，之前已证明CD 95-L在多种肿瘤细胞中介导药物诱导的细胞凋亡，但在阿霉素耐药细胞中CD 95-L的上调被完全阻断。原型半胱天冬酶（ICE/Ced-3蛋白酶）底物聚（ADP-核糖）聚合酶（PARP）在CD 95触发或药物治疗后在敏感的肿瘤细胞中被切割，但在耐药的肿瘤细胞中不被切割。由于未能激活CD 95-L不是由于药物摄取减少或药物外排增加，因此这种类型的耐药涉及非多药耐药（非MDR）机制。这些发现表明，完整的CD 95系统在确定对抗癌治疗的敏感性或耐药性方面起着关键作用。
The molecular mechanisms for sensitivity and resistance of tumor cells towards chemotherapy are only partially understood, In chemosensitive leukemias and solid tumors, anticancer drugs have been shown to induce apoptosis. We previously identified activation of the CD95 (APO-1/Fas) receptor/CD95 ligand (CD95/CD95-L) system as a key mechanism for drug-induced apoptosis. Here, we show that therapeutic concentrations of doxorubicin, methotrexate and cytarabine also induce apoptosis via activation of the CD95 system in primary leukemia cells in vivo, CD95-resistant and doxorubicin-resistant leukemia and neuroblastoma cells display cross-resistance for induction of cell death. Down-regulation of CD95 expression was found in drug-resistant and CD95-resistant cell lines. Furthermore, up-regulation of CD95-L, previously shown to mediate drug-induced apoptosis in a variety of tumor cells, was completely blocked in doxorubicin-resistant cells. The prototype caspase (ICE/Ced-3 protease) substrate, poly(ADP-ribose)polymerase (PARP), was cleaved in sensitive, but not in resistant tumor cells following CD95 triggering or drug treatment. Since failure to activate CD95-L was not due to decreased drug uptake or increased drug efflux, non-multi-drug resistance (non-MDR) mechanisms are involved in this type of resistance. These findings suggested that an intact CD95 system plays a key role in determining sensitivity or resistance towards anticancer therapy.