Dataset Information

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

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.

SUBMITTER: He G

PROVIDER: S-EPMC6310009 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

He Guanping G Ma Yunlong Y Zhu Ye Y Yong Lei L Liu Xiao X Wang Peng P Liang Chen C Yang Chenlong C Zhao Zhigang Z Hai Bao B Pan Xiaoyu X Liu Zhongjun Z Liu Xiaoguang X Mao Chuanbin C

Advanced healthcare materials 20180614 17

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 zin ...[more]

PMID: 29900694

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Project description:Unresectable colorectal liver metastases remain a major unresolved issue and more effective novel regimens are urgently needed. While screening synergistic drug combinations for colon cancer therapy, we identified a novel multidrug treatment for colon cancer: chemotherapeutic agent melphalan in combination with proteasome inhibitor bortezomib and mTOR (mammalian target of rapamycin) inhibitor rapamycin. We investigated the mechanisms of synergistic antitumor efficacy during the multidrug treatment. All experiments were performed with highly metastatic human colon cancer CX-1 and HCT116 cells, and selected critical experiments were repeated with human colon cancer stem Tu-22 cells and mouse embryo fibroblast (MEF) cells. We used immunochemical techniques to investigate a cross-talk between apoptosis and autophagy during the multidrug treatment. We observed that melphalan triggered apoptosis, bortezomib induced apoptosis and autophagy, rapamycin caused autophagy and the combinatorial treatment-induced synergistic apoptosis, which was mediated through an increase in caspase activation. We also observed that mitochondrial dysfunction induced by the combination was linked with altered cellular metabolism, which induced adenosine monophosphate-activated protein kinase (AMPK) activation, resulting in Beclin-1 phosphorylated at Ser 93/96. Interestingly, Beclin-1 phosphorylated at Ser 93/96 is sufficient to induce Beclin-1 cleavage by caspase-8, which switches off autophagy to achieve the synergistic induction of apoptosis. Similar results were observed with the essential autophagy gene, autophagy-related protein 7, -deficient MEF cells. The multidrug treatment-induced Beclin-1 cleavage was abolished in Beclin-1 double-mutant (D133A/D146A) knock-in HCT116 cells, restoring the autophagy-promoting function of Beclin-1 and suppressing the apoptosis induced by the combination therapy. These observations identify a novel mechanism for AMPK-induced apoptosis through interplay between autophagy and apoptosis.

Dataset Information

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

Publications

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

Similar Datasets

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