Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Zhanjiang, China.
Environ Toxicol. 2023 Aug;38(8):1874-1890. doi: 10.1002/tox.23814. Epub 2023 May 6.
Hydroquinone (HQ), one of the main active metabolites of benzene in vivo, 7is commonly used as a surrogate for benzene in in vitro studies and has been shown to be cytotoxic. The aim of this study was to investigate the role of endoplasmic reticulum stress (ERS) in HQ-induced autophagy and apoptosis in human lymphoblastoid cells (TK6) and how activating transcription factor 6 (ATF-6) is involved. We treated TK6 cells with HQ to establish a cytotoxicity model and found that HQ induced cellular ERS, autophagy and apoptosis by Western blot, flow cytometry and transmission electron microscopy. In addition, inhibition of both reactive oxygen species (ROS) and ERS inhibited cellular autophagy and apoptosis, suggesting that ERS may be induced by ROS, which in turn affects autophagy and apoptosis. Our study also found that HQ could inhibit ATF6 expression and mTOR activation. Knockdown of ATF6 enhanced autophagy and apoptosis levels and further inhibited mTOR activation; activation of ATF6 by AA147 enhanced cellular activity, suggesting that ATF6 may affect cellular autophagy and apoptosis through mTOR. In conclusion, our data suggest that ROS mediated ERS may promote autophagy and apoptosis by inhibiting ATF6-mTOR pathway after HQ treatment of TK6 cells.
对苯二酚（HQ）是体内苯的主要活性代谢物之一，常被用作体外研究中苯的替代物，已被证明具有细胞毒性。本研究旨在探讨内质网应激（ERS）在 HQ 诱导人淋巴母细胞（TK6）自噬和凋亡中的作用，以及激活转录因子 6（ATF-6）如何参与其中。我们用 HQ 处理 TK6 细胞，建立细胞毒性模型，发现 HQ 通过 Western blot、流式细胞术和透射电镜诱导细胞 ERS、自噬和凋亡。此外，抑制活性氧（ROS）和 ERS 均可抑制细胞自噬和凋亡，提示 ERS 可能由 ROS 诱导，进而影响自噬和凋亡。我们的研究还发现 HQ 可抑制 ATF6 表达和 mTOR 激活。敲低 ATF6 可增强自噬和凋亡水平，并进一步抑制 mTOR 激活；AA147 激活 ATF6 可增强细胞活力，提示 ATF6 可能通过 mTOR 影响细胞自噬和凋亡。总之，本研究数据表明，ROS 介导的 ERS 可能通过抑制 HQ 处理 TK6 细胞后的 ATF6-mTOR 通路促进自噬和凋亡。
