Involvement of protective autophagy in TRAIL resistance of apoptosis-defective tumor cells
Involvement of protective autophagy in TRAIL resistance of apoptosis-defective tumor cells
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DOI：
10.1074/jbc.m710169200
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发表时间：
2008-07-11
影响因子：
4.8
通讯作者：
Rabinowich, Hannah
中科院分区：
文献类型：
--
作者：
Han, Jie;Hou, Wen;Rabinowich, Hannah
用重组TRAIL或激动性DR 4或DR 5特异性抗体靶向TRAIL受体已被认为是一种有前景的癌症治疗方法，特别是由于肿瘤细胞相对于正常细胞对TRAIL的优先凋亡易感性。然而，许多肿瘤对TRAIL治疗无反应的认识刺激了人们对鉴定凋亡剂的兴趣，当与TRAIL组合使用时，凋亡剂可以使肿瘤细胞对TRAIL介导的凋亡敏感。我们的研究表明，在凋亡信号通路的沿着不同点阻断TRAIL介导的细胞死亡的各种凋亡缺陷将信号级联从默认凋亡转移到细胞保护性自噬。我们还获得的证据表明，抑制这样的TRAIL介导的自噬反应的自噬基因的特异性敲低启动一个有效的线粒体凋亡反应，是caspase-8依赖性。目前，自噬与线粒体凋亡的分子机制尚不清楚。我们的分子机制的分析涉及的转变，从保护性自噬细胞凋亡的响应TRAIL揭示了新的光凋亡的自噬过程中的负调控和它的一些个别组件。
Targeting TRAIL receptors with either recombinant TRAIL or agonistic DR4-or DR5-specific antibodies has been considered a promising treatment for cancer, particularly due to the preferential apoptotic susceptibility of tumor cells over normal cells to TRAIL. However, the realization that many tumors are unresponsive to TRAIL treatment has stimulated interest in identifying apoptotic agents that when used in combination with TRAIL can sensitize tumor cells to TRAIL-mediated apoptosis. Our studies suggest that various apoptosis defects that block TRAIL-mediated cell death at different points along the apoptotic signaling pathway shift the signaling cascade from default apoptosis toward cytoprotective autophagy. We also obtained evidence that inhibition of such a TRAIL-mediated autophagic response by specific knockdown of autophagic genes initiates an effective mitochondrial apoptotic response that is caspase-8-dependent. Currently, the molecular mechanisms linking disabled autophagy to mitochondrial apoptosis are not known. Our analysis of the molecular mechanisms involved in the shift from protective autophagy to apoptosis in response to TRAIL sheds new light on the negative regulation of apoptosis by the autophagic process and by some of its individual components.