Mitochondrial division inhibitor-1 induces mitochondrial hyperfusion and sensitizes human cancer cells to TRAIL-induced apoptosis
Mitochondrial division inhibitor-1 induces mitochondrial hyperfusion and sensitizes human cancer cells to TRAIL-induced apoptosis
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DOI：
10.3892/ijo.2014.2608
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发表时间：
2014-11-01
影响因子：
5.2
通讯作者：
Suzuki-Karasaki, Yoshihiro
中科院分区：
文献类型：
--
作者：
Akita, Mamoru;Suzuki-Karasaki, Miki;Suzuki-Karasaki, Yoshihiro
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）是一种很有前途的肿瘤治疗药物，但某些肿瘤细胞对TRAIL的细胞毒性有抵抗力。因此，克服这种耐药性对于有效的TRAIL治疗是必要的。线粒体形态对于维持细胞功能和存活是重要的，并且受到分裂和融合之间的微妙平衡的调节。然而，线粒体形态动力学在TRAIL诱导的细胞凋亡中的作用尚不清楚。在这里，我们表明，线粒体分裂抑制剂-1（mdivi-1），动力蛋白相关蛋白1（Drp 1）的抑制剂，调节线粒体形态和TRAIL诱导的人癌细胞凋亡。mdivi-1处理（>= 12.5 μ M）在恶性黑色素瘤、肺癌和骨肉瘤细胞中引起剂量和时间依赖性细胞死亡，而不影响正常细胞。mdivi-1还使癌细胞对TRAIL诱导的凋亡敏感。这种增强凋亡发生通过半胱天冬酶依赖的机制，包括线粒体和内质网（ER）的压力途径。Mdivi-1增强线粒体氧化应激，线粒体和ER应激的主要原因，如通过线粒体活性氧水平、线粒体质量和心磷脂氧化的增加所证明的。使用MitoTracker Red CMXRos的活细胞荧光成像显示Mdivi-1引起大量线粒体过度融合。此外，沉默的Drp 1表达也引起线粒体过度融合和敏感的癌细胞TRAIL诱导的凋亡。我们的研究结果表明，癌细胞比正常细胞更容易受到线粒体形态动力学扰动的影响，这种更高的易感性可以被用来选择性地杀死癌细胞并对TRAIL敏感。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer treatment, but some cancer cell types are resistant to TRAIL cytotoxicity. Therefore, overcoming this resistance is necessary for effective TRAIL therapy. Mitochondrial morphology is important for the maintenance of cell function and survival, and is regulated by the delicate balance between fission and fusion. However, the role of mitochondrial morphology dynamics in TRAIL-induced apoptosis is unknown. Here we show that mitochondrial division inhibitor-1 (mdivi-1), an inhibitor of dynamin-related protein1 (Drp1), modulates mitochondrial morphology and TRAIL-induced apoptosis in human cancer cells. mdivi-1 treatment (>= 12.5 mu M) caused dose- and time-dependent cell death in malignant melanoma, lung cancer and osteosarcoma cells, while sparing normal cells. mdivi-1 also sensitized cancer cells to TRAIL-induced apoptosis. This potentiation of apoptosis occurred through a caspase-depependent mechanism including the mitochondrial and endoplasmic reticulum (ER) stress pathways. Mdivi-1 potentiated mitochondrial oxidative stress, a major cause of mitochondrial and ER stresses, as evidenced by increases in mitochondrial reactive oxygen species levels, mitochondrial mass, and cardiolipin oxidation. Live cell fluorescence imaging using MitoTracker Red CMXRos revealed that Mdivi-1 caused substantial mitochondrial hyperfusion. Moreover, silencing of Drp1 expression also caused mitochondrial hyperfusion and sensitized cancer cells to TRAIL-induced apoptosis. Our results suggest that cancer cells are more vulnerable than normal cells to a perturbation in mitochondrial morphology dynamics and that this higher susceptibility can be exploited to selectively kill cancer cells and sensitize to TRAIL.