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Adv Healthc Mater. 2018 Sep;7(17):e1800332. doi: 10.1002/adhm.201800332. Epub 2018 Jun 14.

Cross Talk Between Autophagy and Apoptosis Contributes to ZnO Nanoparticle-Induced Human Osteosarcoma Cell Death.

Author information

1
Department of Orthopedics, Peking University Third Hospital, No. 49, North Garden Street, Haidian District, Beijing, 100191, China.
2
The Center for Pain Medicine, Peking University Third Hospital, No. 49, North Garden Street, Haidian District, Beijing, 100191, China.
3
Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK, 73019, USA.
4
School of Materials Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, China.

Abstract

Killing osteosarcoma cells by zinc oxide nanoparticles (NPs) and its underlying subcellular mechanism are never studied. Here, it is found that the NPs induce cross talk between apoptosis and autophagy, which leads 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.

KEYWORDS:

apoptosis; autophagy; cross talk; human osteosarcoma cells; zinc oxide nanoparticles

PMID:
29900694
PMCID:
PMC6310009
[Available on 2019-09-01]
DOI:
10.1002/adhm.201800332

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