Cross Talk Between Autophagy and Apoptosis Contributes to ZnO Nanoparticle-Induced Human Osteosarcoma Cell Death.
Cross Talk Between Autophagy and Apoptosis Contributes to ZnO Nanoparticle-Induced Human Osteosarcoma Cell Death.
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自噬和细胞凋亡之间的相互作用导致氧化锌纳米粒子诱导的人骨肉瘤细胞死亡
DOI：
10.1002/adhm.201800332
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发表时间：
2018-09
影响因子：
10
通讯作者：
Mao C
中科院分区：
文献类型：
--
作者：
He G;Ma Y;Zhu Y;Yong L;Liu X;Wang P;Liang C;Yang C;Zhao Z;Hai B;Pan X;Liu Z;Liu X;Mao C
氧化锌纳米颗粒（ZnO NPs）杀伤骨肉瘤细胞及其潜在的亚细胞机制尚未被研究。本研究发现NPs诱导细胞凋亡和自噬之间的串扰，从而导致骨肉瘤细胞死亡。具体来说，NP摄取通过诱导自噬体的积累以及溶酶体功能的损害来促进自噬。自噬进一步通过促进锌离子的溶解，使摄取的NPs释放锌离子。这些细胞内锌离子，与那些最初从细胞外NPs释放并流入细胞的锌离子一起，共同靶向并破坏线粒体以产生活性氧（ROS）。然后ROS通过阻断S期抑制细胞增殖，并通过外在和内在途径引发细胞凋亡，最终导致细胞死亡。更重要的是，抑制早期自噬可以通过消除细胞凋亡来恢复细胞活力，而抑制晚期自噬则相反地促进细胞凋亡。相反，抑制细胞凋亡恢复细胞活力的能力有限，但明显增强自噬。值得注意的是，细胞活力在晚期自噬和凋亡抑制剂的联合作用下明显改善。这些发现为骨肉瘤细胞的np定向自噬和凋亡提供了机制上的理解。
Killing osteosarcoma cells by zinc oxide nanoparticles (ZnO NPs) and its underlying sub-cellular mechanism have never been studied. Here we find that the NPs induced crosstalk between apoptosis and autophagy, which lead to osteosarcoma cell death. Specifically, the NP uptake promotes autophagy by inducing accumulation of autophagosomes along with impairment of lysosomal functions. The autophagy further causes the uptaken NPs to release zinc ions by promoting their dissolution. These intracellular zinc ions, together with those that are originally released from the extracellular NPs and flowed into the cells, collectively target and damage mitochondria to produce reactive oxygen species (ROS). Then the ROS inhibit cell proliferation by arresting S phase and trigger apoptosis by extrinsic and intrinsic pathways, ultimately leading to cell death. More importantly, suppression of the early stage autophagy restores cell viability by abolishing apoptosis whereas blockade of the late stage autophagy inversely enhances apoptosis. In contrast, inhibition of apoptosis shows a limited ability to restore cell viability but obviously enhance autophagy. Notably, cell viability is strongly ameliorated by the combination of inhibitors for both the late stage autophagy and the apoptosis. These findings provide a mechanistic understanding of the NP-directed autophagy and apoptosis in osteosarcoma cells.
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