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首页> 外文期刊>Cellular Physiology and Biochemistry >Mechanisms of resistance of human glioma cells to Apo2 ligand/TNF-related apoptosis-inducing ligand
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Mechanisms of resistance of human glioma cells to Apo2 ligand/TNF-related apoptosis-inducing ligand

机译：人脑胶质瘤细胞对Apo2配体/ TNF相关凋亡诱导配体的抗性机制

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Background: Many tumor cells are resistant to Apo2L/TRAIL-induced apoptosis in the absence of inhibitors of protein synthesis. Apo2L/TRAIL, in addition to induction of apoptosis, may therefore also activate survival pathways. Methods: Here we investigated whether such survival pathways mediate resistance to Apo2L.0-induced apoptosis in human glioma cells. Results: Apo2L.0 induced the phosphorylation of ERK1/2, but not of Akt. This effect was unaffected by caspase inhibition. Inhibitors of protein synthesis, PI3 kinase, ERK kinase, NF-kappa B or casein kinase 2 sensitized for Apo2L.0-induced apoptosis to a different extent in a panel of human malignant glioma cell lines. However, none of the sensitizers overcame resistance mediated by ectopic expression of the viral caspase 8 inhibitor, crm-A. Primary glioma cultures were almost completely resistant to Apo2L. 0-induced cell death even in the presence of the inhibitors. Caspase-8 was expressed in these cells whereas only weak expression of DR5 was detected. Transient expression of DR5 conferred sensitivity to Apo2L.0. Conclusion: These data challenge the view that specific cell lines harbour specific mechanisms of resistance to Apo2L/TRAIL. Weak expression of DR5 in primary glioma might limit the therapeutic application of Apo2L/TRAIL in human glioblastoma patients. Copyright (c) 2007 S. Karger AG, Basel.
机译：背景：在没有蛋白质合成抑制剂的情况下，许多肿瘤细胞对Apo2L / TRAIL诱导的细胞凋亡具有抗性。 Apo2L / TRAIL除了诱导凋亡外，还可能因此激活生存途径。方法：在这里，我们调查了这种存活途径是否介导了对Apo2L.0诱导的人胶质瘤细胞凋亡的抗性。结果：Apo2L.0诱导ERK1 / 2磷酸化，而不诱导Akt。该效应不受胱天蛋白酶抑制作用的影响。在一组人类恶性神经胶质瘤细胞系中，蛋白质合成抑制剂，PI3激酶，ERK激酶，NF-κB或酪蛋白激酶2对Apo2L.0诱导的细胞凋亡的敏感性有所不同。但是，没有一种敏化剂能克服由病毒caspase 8抑制剂crm-A的异位表达介导的抗药性。原发性神经胶质瘤培养物几乎完全抵抗Apo2L。 0诱导的细胞死亡，即使存在抑制剂也是如此。 Caspase-8在这些细胞中表达，而仅检测到DR5的弱表达。 DR5的瞬时表达赋予对Apo2L.0的敏感性。结论：这些数据挑战了这样的观点，即特定细胞系具有对Apo2L / TRAIL耐药的特定机制。 DR5在原发性神经胶质瘤中的弱表达可能会限制Apo2L / TRAIL在人胶质母细胞瘤患者中的治疗应用。版权所有（c）2007 S.Karger AG，巴塞尔。

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