The Eighth Affiliated Hospital, Sun Yat-sen University, Shen Zhen, Guangdong, China, 518033.
Int J Med Sci. 2023 Sep 18;20(12):1535-1550. doi: 10.7150/ijms.86409. eCollection 2023.
Multiple myeloma (MM) is an incurable haematological cancer characterized by abnormal proliferation of plasma cells. The promising therapeutic effect of selective inhibitors of nuclear export in MM reveals the broad therapeutic prospects of nuclear localization intervention. Sterol regulatory element binding protein 2 (SREBP2) is a lipid regulatory molecule that has been implicated in the effect of drug therapy for MM. SREBP2 has been reported to be regulated by the antimalarial drug artesunate (ART) through alteration of its nuclear localization and has been shown to inhibit ferroptosis in other tumours. However, the mechanism through which this might occur has not been clarified in MM. Our study aimed to explore whether ART can induce ferroptosis in MM through nuclear localization of SREBP2. To evaluate whether ferroptosis is induced by treatment with ART in myeloma, we used two types of myeloma cell lines. We first used a series of molecular approaches and other techniques to investigate the impact of ART on cell growth, production of reactive oxygen species (ROS), Fe levels, lipid peroxidation and expression of genes related to ferroptosis. Then, we further explored the mechanism through which ferroptosis may occur in these cells and the relationship between ferroptosis and the nuclear localization of SREBP2. Upregulation of ROS, Fe, and lipid peroxidation as well as inhibition of cell growth were observed in myeloma cells after treatment with ART. Expression of acyl CoA synthase long chain family member 4 (ACSL4) was increased, while glutathione peroxidase 4 (GPX4) expression was reduced in cells treated with ART. ART-induced cell death could be reversed by ferropstatin-1 (Fer-1) and deferoxamine mesylate (DFO). Nuclear localization of SREBP2 in myeloma cells was inhibited, accompanied by downregulation of isopentenyl pyrophosphate (IPP) and GPX4, after treatment with ART. In conclusion, our study demonstrated that the antimalarial drug ART can inhibit nuclear localization of SREBP2, downregulate IPP and GPX4, and eventually trigger ferroptosis in myeloma cells. Through this study, we hope to establish a correlation between nuclear localization pathways and mediation of ferroptosis in myeloma cells and provide an innovative direction for exploration-related therapy.
多发性骨髓瘤（MM）是一种不可治愈的血液系统癌症，其特征是浆细胞异常增殖。核输出选择性抑制剂在 MM 中的有希望的治疗效果揭示了核定位干预的广阔治疗前景。固醇调节元件结合蛋白 2（SREBP2）是一种脂质调节分子，已被牵连到 MM 的药物治疗效果中。已经报道青蒿琥酯（ART）通过改变其核定位来调节 SREBP2，并且已经显示在其他肿瘤中抑制铁死亡。然而，在 MM 中，其发生的机制尚不清楚。我们的研究旨在探讨 ART 是否可以通过 SREBP2 的核定位诱导 MM 中的铁死亡。为了评估 ART 在骨髓瘤中是否通过 SREBP2 的核定位诱导铁死亡，我们使用了两种骨髓瘤细胞系。我们首先使用一系列分子方法和其他技术来研究 ART 对细胞生长、活性氧（ROS）产生、Fe 水平、脂质过氧化和与铁死亡相关的基因表达的影响。然后，我们进一步探讨了这些细胞中可能发生铁死亡的机制以及铁死亡与 SREBP2 核定位之间的关系。ART 处理后，骨髓瘤细胞中观察到 ROS、Fe 和脂质过氧化的上调以及细胞生长的抑制。ACSL4 的表达增加，而 ART 处理的细胞中 GPX4 的表达减少。用铁死亡抑制剂 Ferrostatine-1（Fer-1）和甲磺酸去铁胺（DFO）可逆转 ART 诱导的细胞死亡。ART 处理后，骨髓瘤细胞中 SREBP2 的核定位被抑制，同时异戊烯焦磷酸（IPP）和 GPX4 的表达下调。总之，我们的研究表明，抗疟药物 ART 可以抑制 SREBP2 的核定位，下调 IPP 和 GPX4，最终在骨髓瘤细胞中引发铁死亡。通过这项研究，我们希望在骨髓瘤细胞中建立核定位途径与铁死亡之间的相关性，并为相关治疗探索提供新的方向。
