Activation of autophagy by elevated reactive oxygen species rather than released silver ions promotes cytotoxicity of polyvinylpyrrolidone-coated silver nanoparticles in hematopoietic cells
Activation of autophagy by elevated reactive oxygen species rather than released silver ions promotes cytotoxicity of polyvinylpyrrolidone-coated silver nanoparticles in hematopoietic cells
复制标题
通过升高的活性氧而不是释放的银离子来激活自噬可促进造血细胞中聚乙烯吡咯烷酮包被的银纳米颗粒的细胞毒性
作者：
Lingying Zhu;Dawei Guo;Lili Sun;Zhihai Huang;Xiuyan Zhang;Wenjuan Ma;Jie Wu;Lun Xiao;Yun Zhao;Ning Gu
银纳米粒子 (AgNP) 因其抗菌活性而成为商业产品中最常用的工程纳米材料。此前，我们已经证明，聚乙烯吡咯烷酮（PVP）包被的AgNPs对人骨髓性白血病细胞具有抗白血病作用；然而，AgNPs是否能够触发正常造血细胞的自噬以及自噬在AgNP诱导的细胞毒性中的作用仍不清楚。在本研究中，我们观察到AgNPs被小鼠pro-B细胞（Ba/F3）摄取，然后促进自噬体的积累，这是诱导自噬而不是阻断自噬流的结果。 AgNPs 通过产生活性氧 (ROS) 和释放银离子，以剂量依赖性方式诱导细胞毒性，并伴有细胞凋亡和 DNA 损伤。 ROS 介导的 mTOR 信号通路负责诱导自噬。更重要的是，通过添加 3-甲基腺嘌呤 (3-MA) 或沉默 Atg5 来抑制自噬，可显着减弱 Ba/F3 中 AgNP 的细胞毒性。这些发现表明，自噬参与了正常造血细胞中 PVP 包被的 AgNP 的细胞毒性，并且抑制自噬是在 AgNP 处理后保护正常造血细胞的一种新颖且有效的策略。
Silver nanoparticles (AgNPs) are the most commonly used engineered nanomaterials in commercialized products because of their antimicrobial activity. Previously, we have shown that polyvinylpyrrolidone (PVP)-coated AgNPs have an anti-leukemia effect against human myeloid leukemia cells; however, whether AgNPs are able to trigger autophagy in normal hematopoietic cells and the role of autophagy in AgNP-induced cytotoxicity remain unclear. In the current study, we observed that AgNPs were taken up by murine pro-B cells (Ba/F3), and then promoted accumulation of autophagosomes, which resulted from the induction of autophagy rather than the blockade of autophagic flux. AgNPs induced cytotoxicity in a dose-dependent manner accompanied by apoptosis and DNA damage through the production of reactive oxygen species (ROS) and the release of silver ions. The ROS-mediated mTOR signaling pathway was responsible for the induction of autophagy. More importantly, the inhibition of autophagy with the addition of 3-methyladenine (3-MA) or silencing of Atg5 significantly attenuated the cytotoxicity of AgNPs in Ba/F3. These findings suggest that autophagy is involved in the cytotoxicity of PVP-coated AgNPs in normal hematopoietic cells, and the inhibition of autophagy is a novel and potent strategy to protect normal hematopoietic cells upon treatment with AgNPs.