Tumor-selective mitochondrial network collapse induced by atmospheric gas plasma-activated medium.
Tumor-selective mitochondrial network collapse induced by atmospheric gas plasma-activated medium.
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DOI：
10.18632/oncotarget.7889
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发表时间：
2016-04-12
期刊：
影响因子：
--
通讯作者：
Suzuki-Karasaki Y
中科院分区：
文献类型：
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作者：
Saito K;Asai T;Fujiwara K;Sahara J;Koguchi H;Fukuda N;Suzuki-Karasaki M;Soma M;Suzuki-Karasaki Y
非热大气等离子体（AGP）对恶性细胞具有细胞毒性，对正常细胞具有最小的细胞毒性。然而，其肿瘤选择性细胞毒性的机制仍不清楚。在此，我们报告 AGP 激活培养基会增加一组人类癌细胞中不依赖于半胱天冬酶的细胞死亡和线粒体网络崩溃，但在非转化细胞中则不会。 AGP 照射刺激 AGP 激活培养基中活性氧 (ROS) 的产生，进而产生稳定的 ROS，很可能是过氧化氢 (H2O2)，激活细胞内 ROS 的产生和线粒体 ROS (mROS) 的积累。在 AGP 激活的培养基中培养会导致细胞死亡和线粒体过度断裂和聚集，而这些反应会被 ROS 清除剂抑制。 AGP 激活培养基还以肿瘤特异性方式增加动力相关蛋白 1 依赖性线粒体裂变，并且 H2O2 给药也显示出类似的效果。此外，肿瘤细胞对线粒体网络崩溃的脆弱性似乎是由于它们对 AGP 激活介质或 H2O2 诱导的 mROS 积累具有更高的敏感性。目前的研究结果扩展了我们之前对死亡受体介导的肿瘤选择性细胞杀伤的观察，并强化了线粒体网络重塑作为肿瘤选择性癌症治疗的强大靶标的重要性。
Non-thermal atmospheric gas plasma (AGP) exhibits cytotoxicity against malignant cells with minimal cytotoxicity toward normal cells. However, the mechanisms of its tumor-selective cytotoxicity remain unclear. Here we report that AGP-activated medium increases caspase-independent cell death and mitochondrial network collapse in a panel of human cancer cells, but not in non-transformed cells. AGP irradiation stimulated reactive oxygen species (ROS) generation in AGP-activated medium, and in turn the resulting stable ROS, most likely hydrogen peroxide (H2O2), activated intracellular ROS generation and mitochondrial ROS (mROS) accumulation. Culture in AGP-activated medium resulted in cell death and excessive mitochondrial fragmentation and clustering, and these responses were inhibited by ROS scavengers. AGP-activated medium also increased dynamin-related protein 1-dependent mitochondrial fission in a tumor-specific manner, and H2O2 administration showed similar effects. Moreover, the vulnerability of tumor cells to mitochondrial network collapse appeared to result from their higher sensitivity to mROS accumulation induced by AGP-activated medium or H2O2. The present findings expand our previous observations on death receptor-mediated tumor-selective cell killing and reinforce the importance of mitochondrial network remodeling as a powerful target for tumor-selective cancer treatment.