Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system
Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system
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实体瘤细胞体外化疗敏感性与CD95系统的激活有关
DOI：
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发表时间：
1998
影响因子：
6.4
通讯作者：
K. Debatin
中科院分区：
文献类型：
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作者：
S. Fulda;M. Los;C. Friesen;K. Debatin
我们已经确定 CD95 系统是化疗诱导的白血病和神经母细胞瘤细胞凋亡的关键介质。在这里，我们报告各种实体瘤细胞系对药物诱导的细胞死亡的敏感性与 CD95 系统的激活相对应。药物治疗后，在化学敏感的肿瘤细胞（霍奇金、尤文氏肉瘤、结肠癌和小细胞肺癌）中发现了 CD95 配体（CD95-L）和 caspase 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）中却没有发现。使用 F(ab')2 抗 CD95 抗体片段阻断 CD95 显着减少药物诱导的细胞凋亡，表明药物触发的细胞凋亡依赖于 CD95-L/受体相互作用。此外，药物治疗诱导 CD95 表达，从而增加对 CD95 诱导的细胞凋亡的敏感性。药物诱导的细胞凋亡主要取决于半胱天冬酶（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 强烈减少药物介导的细胞凋亡。 Caspases 的原型底物聚（ADP-核糖）聚合酶在药物处理后被裂解，表明 CD95-L 通过激活 Caspases 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完整的细胞凋亡途径，涉及 CD95 系统的激活和半胱天冬酶的加工。我们的发现可能对提高敏感性和克服实体瘤耐药性的新治疗方法具有重要意义。国际。 J. Cancer 76:105–114, 1998.© 1998 Wiley‐Liss, Inc.
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. Int. J. Cancer 76:105–114, 1998.© 1998 Wiley‐Liss, Inc.
影响因子：
56.9
作者：
LOWE, SW;BODIS, S;JACKS, T
通讯作者：
JACKS, T