VPS34 regulates dynamin to determine the endocytosis of mitochondria-targeted zinc oxide nanoparticles in human osteosarcoma cells. Issue 11 (8th March 2021)

• Record Type: Journal Article
• Authors: Pan, Xiaoyu; He, Guanping; Hai, Bao; Liu, Yu; Bian, Lei; Yong, Lei; Zhang, Hanwen; Yang, Chenlong; Du, Chuanchao; Mao, Tianli; Ma, Yunlong; Jia, Fei; Dou, Xinyu; Zhai, Shuheng; Liu, Xiaoguang
• Is Part Of: Journal of materials chemistry. Volume 9:Issue 11(2021)
• Page Start: 2641
• Page End: 2655
• Publication Date: 2021-03-08
• Subjects: Materials -- Periodicals; Chemistry, Analytic -- Periodicals; Biomedical materials -- Research -- Periodicals; 543.0284
• DOI: 10.1039/d1tb00226k
• Languages: English
• ISSNs: 2050-750X

Abstract

Abstract : ZnO NPs enter into osteosarcoma cells via VPS34/dynamin 2 pathway and accumulated in mitochondria, initiating mitophagy and subsequent apoptosis. Abstract : In our previous study, zinc oxide nanoparticles (ZnO NPs) presented satisfying therapeutic effects with cancer cell selectivity in osteosarcoma cells and, thus, have been considered as a potential nanomedicine for human osteosarcoma treatment. However, the poorly investigated internalization process, including their endocytic pathway into tumor cells and intracellular fate, limits the clinical application. Here, we further clarified these aspects. First, ZnO NPs were rapidly internalized by osteosarcoma cells and accumulated in mitochondria, before being entrapped into lysosomes. Second, dynasore (a dynamin inhibitor) was demonstrated to be the most effective in blocking ZnO NP uptake and rescuing ZnO NP-induced osteosarcoma cell autophagic death and apoptosis. Third, we confirmed the key role of dynamin 2 in ZnO NP endocytosis and subsequent autophagic cell death in vitro and in vivo . Furthermore, we proved that VPS34 transferred from cell cytoplasm to cell membrane to interact with dynamin under ZnO NP treatment. Altogether, combined with our previous study, the current research further revealed that ZnO NPs entered human osteosarcoma cells through the VPS34/dynamin 2-dependent endocytic pathway, directly targeting and damaging the mitochondria before being entrapped into the lysosomes, thereby initiating mitophagy-Zn 2+ -reactive oxygen species-mitophagy axis mediated cell apoptosis.