Distinct effects of TRAIL on the mitochondrial network in human cancer cells and normal cells: role of plasma membrane depolarization.
Distinct effects of TRAIL on the mitochondrial network in human cancer cells and normal cells: role of plasma membrane depolarization.
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TRAIL对人类癌细胞和正常细胞线粒体网络的独特影响：质膜去极化的作用。
DOI：
10.18632/oncotarget.4268
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发表时间：
2015-08-28
期刊：
影响因子：
--
通讯作者：
Soma M
中科院分区：
文献类型：
--
作者：
Suzuki-Karasaki Y;Fujiwara K;Saito K;Suzuki-Karasaki M;Ochiai T;Soma M
Apo2配体/肿瘤坏死因子相关凋亡诱导配体（Apo2L/TRAIL）具有肿瘤选择性的细胞毒性，是一种很有前景的抗癌药物。在这里，我们报道TRAIL对恶性细胞和正常细胞的线粒体网络有不同的影响。活细胞成像显示，多种人类癌细胞系和正常细胞对TRAIL和死亡受体激动剂表现出两种不同的线粒体反应模式。肿瘤细胞内的线粒体在毒性刺激下分裂成点状和聚集。在4小时观察到线粒体断裂，然后随着时间的推移变得更加明显，并且与凋亡细胞死亡有关。相比之下，正常细胞（如黑素细胞和成纤维细胞）内的线粒体即使受到有毒刺激，也只是适度地缩短。尽管TRAIL激活了动力蛋白相关蛋白1 （Drp1）依赖的线粒体分裂，但通过敲低Drp1或使用Drp1抑制剂mdivi-1抑制这一过程，可增强TRAIL诱导的细胞凋亡、线粒体断裂和聚集。此外，线粒体活性氧（ROS）介导的去极化加速了肿瘤细胞中线粒体网络的异常，而在正常细胞中则没有，TRAIL在恶性细胞中引起的线粒体ROS积累和去极化水平高于正常细胞。我们的研究结果表明，肿瘤细胞比正常细胞更容易发生氧化应激和去极化，因此更容易受到线粒体网络异常的影响，这种脆弱性可能与TRAIL靶向肿瘤杀伤有关。
Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a promising anticancer drug due to its tumor-selective cytotoxicity. Here we report that TRAIL exhibits distinct effects on the mitochondrial networks in malignant cells and normal cells. Live-cell imaging revealed that multiple human cancer cell lines and normal cells exhibited two different modes of mitochondrial responses in response to TRAIL and death receptor agonists. Mitochondria within tumor cells became fragmented into punctate and clustered in response to toxic stimuli. The mitochondrial fragmentation was observed at 4 h, then became more pronounced over time, and associated with apoptotic cell death. In contrast, mitochondria within normal cells such as melanocytes and fibroblasts became only modestly truncated, even when they were treated with toxic stimuli. Although TRAIL activated dynamin-related protein 1 (Drp1)-dependent mitochondrial fission, inhibition of this process by Drp1 knockdown or with the Drp1 inhibitor mdivi-1, potentiated TRAIL-induced apoptosis, mitochondrial fragmentation, and clustering. Moreover, mitochondrial reactive oxygen species (ROS)-mediated depolarization accelerated mitochondrial network abnormalities in tumor cells, but not in normal cells, and TRAIL caused higher levels of mitochondrial ROS accumulation and depolarization in malignant cells than in normal cells. Our findings suggest that tumor cells are more prone than normal cells to oxidative stress and depolarization, thereby being more vulnerable to mitochondrial network abnormalities and that this vulnerability may be relevant to the tumor-targeting killing by TRAIL.