Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression.
Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression.
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发表时间：
2001-02
期刊：
影响因子：
11.2
通讯作者：
A. Eggert;M. Grotzer;T. Zuzak;B. Wiewrodt;R. Ho;N. Ikegaki;G. Brodeur
中科院分区：
文献类型：
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作者：
A. Eggert;M. Grotzer;T. Zuzak;B. Wiewrodt;R. Ho;N. Ikegaki;G. Brodeur
细胞凋亡通路的紊乱可能参与神经母细胞瘤(NB)肿瘤的形成、消退和治疗耐药。肿瘤坏死因子相关的凋亡诱导配体(TRAIL)是一种有效的肿瘤细胞系凋亡诱导剂，而正常细胞对TRAIL介导的细胞凋亡不敏感。在本研究中，我们分析了TRAIL及其激动型和拮抗型受体的表达和功能，以及细胞FLICE样抑制蛋白和caspase-2、-3、-8、-9和-10在18个NB细胞系中的表达。半定量RT-PCR显示TRAIL-R2和TRAIL-R3是NB细胞使用的主要TRAIL受体。对TRAIL诱导的细胞凋亡的敏感性与TRAIL受体的mRNA表达或细胞内的FLICE样抑制蛋白无关。令人惊讶的是，在18个NB细胞系中，只有5个细胞株有caspase-8和caspase-10mRNA的表达。有趣的是，只有这五个NB细胞系对TRAIL以时间和剂量依赖的方式诱导的细胞凋亡敏感。经5-氮-2‘-脱氧胞苷处理后，耐药细胞株caspase-8的mRNA和蛋白表达恢复，TRAIL敏感性恢复，提示基因甲基化参与了caspase失活。TRAIL系统似乎在表达caspase-8和/或caspase-10的NB细胞中起作用。由于许多细胞毒药物诱导caspase依赖的细胞凋亡，caspase-8和/或caspase-10的表达缺失可能是耐药的一个重要机制。
Disruption of apoptotic pathways may be involved in tumor formation, regression, and treatment resistance of neuroblastoma (NB). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in cancer cell lines, whereas normal cells are not sensitive to TRAIL-mediated apoptosis. In this study we analyzed the expression and function of TRAIL and its agonistic and antagonistic receptors as well as expression of cellular FLICE-like inhibitory protein and caspase-2, -3, -8, -9, and -10 in 18 NB cell lines. Semiquantitative RT-PCR revealed that TRAIL-R2 and TRAIL-R3 are the main TRAIL-receptors used by NB cells. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cellular FLICE-like inhibitory protein. Surprisingly, caspase-8 and caspase-10 mRNA expression was detected in only 5 of 18 NB cell lines. Interestingly, only these five NB cell lines were susceptible to TRAIL-induced apoptosis in a time- and dose-dependent manner. Treatment with 5-aza-2'-deoxycytidine restored mRNA and protein expression of caspase-8 and TRAIL sensitivity of resistant cell lines, suggesting that gene methylation is involved in caspase inactivation. The TRAIL system seems to be functional in NB cells expressing caspase-8 and/or caspase-10. Because many cytotoxic drugs induce caspase-dependent apoptosis, failure to express caspase-8 and/or caspase-10 might be an important mechanism of resistance to chemotherapy in NB.