The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, Guizhou Medical University, Guiyang, China.
Environ Toxicol. 2020 Oct;35(10):1100-1113. doi: 10.1002/tox.22946. Epub 2020 Jun 7.
Chronic exposure to arsenic remains a worldwide environmental health issue, affecting hundreds of millions of people. Although, arsenic-induced oxidative stress and apoptosis have been determined, the underlying apoptosis mechanism has not been fully elucidated yet. Oxidative stress integrated-ER stress plays an important role in Life-and-Death decision of cells. The current study was to investigate whether NaAsO utilizes oxidative stress integrated-ER stress signaling to exert pro-apoptotic activity in L-02 cells. Results showed that death receptor 5 (DR5) was a mediator of NaAsO -induced apoptosis by enhancing construction of the death-inducing signaling complex (DISC). NaAsO -sensitized DR5 elevation required maintainable transcription and its transcription factor C/EBP homologous protein (CHOP). Further results showed that NaAsO increased expression in biomarker of endoplasmic reticulum (ER) stress and activated the protein kinase R-like ER kinase (PERK)-eukaryotic translation initiation 2α (eIF2α)-activating transcription factor 4 (ATF4) pathway. PERK inhibitor and ATF4 siRNA significantly attenuated NaAsO -induced CHOP and DR5 expressions. In addition, the antioxidant N-acetyl-l-cysteine (NAC) treatment led to amelioration of NaAsO -induced production of reactive oxygen species (ROS) and some ER stress- and apoptosis- related protein levels and cell viability. Taken together, the results indicate that ROS-mediated PERK-eIF2α-ATF4 pathway activated by NaAsO is the critical upstream event for subsequent apoptosis induction via regulating CHOP-DR5 signaling in L-02 cells when chronic exposure to arsenic, and support that antioxidants might be potential therapeutic agents for preventing or delaying the onset and progress of arsenic-induced hepatotoxicity.
慢性砷暴露仍然是一个全球性的环境健康问题，影响着数亿人。尽管已经确定了砷诱导的氧化应激和细胞凋亡，但潜在的凋亡机制尚未完全阐明。氧化应激与内质网应激的整合在细胞生死抉择中起着重要作用。本研究旨在探讨亚砷酸钠（NaAsO）是否通过氧化应激与内质网应激信号通路发挥促凋亡活性。结果表明，死亡受体 5（DR5）是 NaAsO 诱导细胞凋亡的中介，通过增强诱导信号复合物（DISC）的构建来发挥作用。NaAsO 敏化 DR5 升高需要维持转录及其转录因子 C/EBP 同源蛋白（CHOP）。进一步的结果表明，NaAsO 增加内质网（ER）应激生物标志物的表达，并激活蛋白激酶 R 样内质网激酶（PERK）-真核起始因子 2α（eIF2α）-激活转录因子 4（ATF4）通路。PERK 抑制剂和 ATF4 siRNA 显著减弱了 NaAsO 诱导的 CHOP 和 DR5 表达。此外，抗氧化剂 N-乙酰-L-半胱氨酸（NAC）处理可改善 NaAsO 诱导的活性氧（ROS）产生以及一些 ER 应激和凋亡相关蛋白水平和细胞活力。综上所述，这些结果表明，ROS 介导的 PERK-eIF2α-ATF4 通路被 NaAsO 激活，是慢性砷暴露后诱导 L-02 细胞凋亡的关键上游事件，通过调节 CHOP-DR5 信号通路。这支持抗氧化剂可能是预防或延迟砷诱导肝毒性发生和进展的潜在治疗剂。
