Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China.
Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China.
Acta Pharmacol Sin. 2021 Oct;42(10):1690-1702. doi: 10.1038/s41401-021-00700-w. Epub 2021 Jun 10.
Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and HO via Fenton reaction, in which the role of activating transcription factor 3 (ATF3) remains elusive. Brucine is a weak alkaline indole alkaloid extracted from the seeds of Strychnos nux-vomica, which has shown potent antitumor activity against various tumors, including glioma. In this study, we showed that brucine inhibited glioma cell growth in vitro and in vivo, which was paralleled by nuclear translocation of ATF3, lipid peroxidation, and increases of iron and HO. Furthermore, brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine (500 μM) or improved by ferric ammonium citrate (500 μM). Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1 (50 μM) or liproxstatin-1 (30 μM) rescued brucine-induced glioma cell death. Moreover, knockdown of ATF3 prevented brucine-induced accumulation of iron and HO and glioma cell death. We revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER stress. ATF3 promoted brucine-induced HO accumulation via upregulating NOX4 and SOD1 to generate HO on one hand, and downregulating catalase and xCT to prevent HO degradation on the other hand. HO then contributed to brucine-triggered iron increase and transferrin receptor upregulation, as well as lipid peroxidation. This was further verified by treating glioma cells with exogenous HO alone. Moreover, HO reversely exacerbated brucine-induced ER stress. Taken together, ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing HO and iron.
铁死亡是一种铁依赖性脂质过氧化过程，由亚铁离子和 HO 通过芬顿反应引发，而激活转录因子 3（ATF3）在其中的作用仍不清楚。马钱子碱是从马钱子种子中提取的弱碱性吲哚生物碱，对包括神经胶质瘤在内的多种肿瘤具有很强的抗肿瘤活性。在本研究中，我们表明马钱子碱在体外和体内抑制神经胶质瘤细胞生长，同时伴随着 ATF3 的核转位、脂质过氧化和铁及 HO 的增加。此外，用去铁胺（500 μM）螯合细胞内铁或用柠檬酸铁铵（500 μM）改善铁水平时，马钱子碱诱导的脂质过氧化受到抑制或加剧。用亲脂性抗氧化剂 ferrostatin-1（50 μM）或 liproxstatin-1（30 μM）抑制脂质过氧化可挽救马钱子碱诱导的神经胶质瘤细胞死亡。此外，敲低 ATF3 可防止马钱子碱诱导的铁和 HO 积累以及神经胶质瘤细胞死亡。我们揭示了马钱子碱通过激活内质网应激诱导 ATF3 的上调和核转位。ATF3 通过上调 NOX4 和 SOD1 一方面促进 HO 的积累，另一方面下调过氧化氢酶和 xCT 以防止 HO 的降解，从而促进马钱子碱诱导的 HO 增加和转铁蛋白受体上调以及脂质过氧化。这一点通过用外源性 HO 单独处理神经胶质瘤细胞得到了进一步证实。此外，HO 反过来加剧了马钱子碱诱导的内质网应激。总之，ATF3 通过增加 HO 和铁促进马钱子碱诱导的神经胶质瘤细胞铁死亡。
