Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2.
Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2.
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神经母细胞瘤中 Fas 介导的细胞凋亡需要线粒体激活，并受到 FLICE 抑制剂蛋白和 Bcl-2 的抑制。
作者：
V. Poulaki;N. Mitsiades;M. Romero;M. Tsokos
Fas介导的细胞凋亡通过Fas依赖性或非依赖性途径进行，并且在耐药细胞中缺乏。神经母细胞瘤是一种常见的儿科恶性肿瘤，通常会产生耐药性，并且具有沉默的半胱天冬酶8（FLICE）基因，该基因与Fas和耐药性相关。我们报告说，除了caspase 8，这是缺乏在大约三分之一的26例神经母细胞瘤的情况下，在这项研究中，其他蛋白质，如bcl-2和FLICE抑制蛋白（FLIP），是同样重要的，在赋予Fas耐药神经母细胞瘤细胞。bcl-2和FLIP在神经母细胞瘤组织中均有表达。我们的体外研究表明，FLIP被募集到死亡诱导信号复合物中，并干扰神经母细胞瘤细胞中半胱天冬酶8的募集。bcl-2抑制了线粒体的活化，但它也通过结合和隔离caspase 8降低了游离细胞质水平，从而通过线粒体上游的一种新的抗凋亡机制发挥作用。在体外下调bcl-2的反义寡核苷酸允许释放细胞色素c从线粒体和激活caspase 8和3后Fas激活，以及敏感的神经母细胞瘤细胞Fas介导的凋亡。由于同时存在线粒体阻滞，FLIP的下调仅具有适度的凋亡效应。然而，bcl-2和FLIP反义寡核苷酸联合治疗在体外神经母细胞瘤细胞中具有统计学显著的协同作用，逆转了Fas耐药。这些数据表明，Fas介导的神经母细胞瘤细胞的凋亡是依赖性的，并抑制在线粒体水平和caspase 8激活的水平。因此，针对bcl-2和FLIP的基因靶向治疗可能逆转Fas耐药，并证明可用于治疗耐药神经母细胞瘤。
Fas-mediated apoptosis proceeds though mitochondria-dependent or -independent pathways and is deficient in drug-resistant cells. Neuroblastoma, a common pediatric malignancy, often develops drug-resistance and has a silenced caspase 8 (FLICE) gene, which has been associated with Fas- and drug-resistance. We report that besides caspase 8, which was absent in approximately one-third of 26 neuroblastoma cases in this study, other proteins such as bcl-2 and FLICE-inhibitory protein (FLIP), are equally important in conferring Fas-resistance to neuroblastoma cells. Both bcl-2 and FLIP were frequently expressed in neuroblastoma tissues. Our in vitro studies showed that FLIP was recruited to the death-inducing signaling complex and interfered with the recruitment of caspase 8 in neuroblastoma cells. bcl-2 inhibited the activation of the mitochondria; but it also lowered the free cytoplasmic levels of caspase 8 by binding and sequestering it, thus acting through a novel antiapoptotic mechanism upstream of the mitochondria. In vitro down-regulation of bcl-2 with antisense oligonucleotides allowed the release of cytochrome c from mitochondria and the activation of caspases 8 and 3 upon Fas activation as well as sensitized neuroblastoma cells to Fas-mediated apoptosis. Down-regulation of FLIP had only a modest apoptotic effect because of the coexistent mitochondrial block. However, combined treatment with bcl-2 and FLIP antisense oligonucleotides had a statistically significant synergistic effect reversing Fas-resistance in neuroblastoma cells in vitro. These data indicate that Fas-mediated apoptosis in neuroblastoma cells is mitochondria-dependent and inhibited both at the mitochondrial level and at the level of caspase 8 activation. Thus, gene-targeting therapies for bcl-2 and FLIP may reverse Fas-resistance and prove useful in the treatment of drug-resistant neuroblastomas.
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DOI：
--
发表时间：
1999-02
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
D. Tillman;I. Peták;J. Houghton
通讯作者：
D. Tillman;I. Peták;J. Houghton
影响因子：
11.2
作者：
M. Dole;G. Núñez;Audrea K. Merchant;J. Maybaum;C. Rode;C. Bloch;V. Castle
通讯作者：
M. Dole;G. Núñez;Audrea K. Merchant;J. Maybaum;C. Rode;C. Bloch;V. Castle
影响因子：
11.2
作者：
A. Eggert;M. Grotzer;T. Zuzak;B. Wiewrodt;R. Ho;N. Ikegaki;G. Brodeur
通讯作者：
A. Eggert;M. Grotzer;T. Zuzak;B. Wiewrodt;R. Ho;N. Ikegaki;G. Brodeur
bcl2 原癌基因在神经母细胞瘤和其他人类神经源肿瘤细胞系中的差异表达。
影响因子：
11.2
作者：
Reed,JC;Meister,L;Tanaka,S;Cuddy,M;Yum,S;Geyer,C;Pleasure,D
通讯作者：
Pleasure,D
影响因子：
2.4
作者：
Cernaianu, Grigore;Brandmaier, Philipp;Troebs, Ralf B.
通讯作者：
Troebs, Ralf B.