Fulda S, Los M, Friesen C, Debatin K M
Hematology/Oncology, University Children's Hospital, Ulm, Germany.
Int J Cancer. 1998 Mar 30;76(1):105-14. doi: 10.1002/(sici)1097-0215(19980330)76:1<105::aid-ijc17>3.0.co;2-b.
We have identified the CD95 system as a key mediator of chemotherapy-induced apoptosis in leukemia and neuroblastoma cells. Here, we report that sensitivity of various solid tumor cell lines for drug-induced cell death corresponds to activation of the CD95 system. Upon drug treatment, strong induction of CD95 ligand (CD95-L) and caspase activity were found in chemosensitive tumor cells (Hodgkin, Ewing's sarcoma, colon carcinoma and small cell lung carcinoma) but not in tumor cells which responded poorly to drug treatment (breast carcinoma and renal cell carcinoma). Blockade of CD95 using F(ab')2 anti-CD95 antibody fragments markedly reduced drug-induced apoptosis, suggesting that drug-triggered apoptosis depended on CD95-L/receptor interaction. Moreover, drug treatment induced CD95 expression, thereby increasing sensitivity for CD95-induced apoptosis. Drug-induced apoptosis critically depended on activation of caspases (ICE/Ced-3-like proteases) since the broad-spectrum inhibitor of caspases zVAD-fmk strongly reduced drug-mediated apoptosis. The prototype substrate of caspases, poly(ADP-ribose) polymerase, was cleaved upon drug treatment, suggesting that CD95-L triggered autocrine/paracrine death via activation of caspases. Our data suggest that chemosensitivity of solid tumor cells depends on intact apoptosis pathways involving activation of the CD95 system and processing of caspases. Our findings may have important implications for new treatment approaches to increase sensitivity and to overcome resistance of solid tumors.
我们已确定CD95系统是白血病和神经母细胞瘤细胞中化疗诱导凋亡的关键介质。在此，我们报告各种实体瘤细胞系对药物诱导细胞死亡的敏感性与CD95系统的激活相对应。药物处理后，在化疗敏感的肿瘤细胞（霍奇金淋巴瘤、尤因肉瘤、结肠癌和小细胞肺癌）中发现了CD95配体（CD95-L）和半胱天冬酶活性的强烈诱导，但在对药物治疗反应不佳的肿瘤细胞（乳腺癌和肾细胞癌）中未发现。使用F(ab')2抗CD95抗体片段阻断CD95可显著降低药物诱导的凋亡，表明药物触发的凋亡依赖于CD95-L/受体相互作用。此外，药物处理诱导了CD95的表达，从而增加了对CD95诱导凋亡的敏感性。药物诱导的凋亡严重依赖于半胱天冬酶（ICE/Ced-3样蛋白酶）的激活，因为半胱天冬酶的广谱抑制剂zVAD-fmk强烈降低了药物介导的凋亡。半胱天冬酶的原型底物聚（ADP-核糖）聚合酶在药物处理后被切割，表明CD95-L通过激活半胱天冬酶触发自分泌/旁分泌死亡。我们的数据表明实体瘤细胞的化疗敏感性取决于涉及CD95系统激活和半胱天冬酶加工的完整凋亡途径。我们的发现可能对提高实体瘤敏感性和克服耐药性的新治疗方法具有重要意义。
