Institute of Biochemistry and Molecular Biology and School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China.
DNA Cell Biol. 2022 Aug;41(8):705-715. doi: 10.1089/dna.2021.1145. Epub 2022 Jun 10.
The molecular mechanisms and role of ferroptosis in tumor drug resistance remain unclear. In this study, we found that multidrug-resistant (MDR) K562/adriamycin (ADM) leukemia cells possessed higher glutathione (GSH) levels and iron-regulatory protein 2 (IRP2), transferrin receptor, ferritin heavy chain 1 (FTH1), and peroxidase-4 (GPX4) expression than parental drug-sensitive K562 leukemia cells. These elevations might have increased the antioxidant ability of K562/ADM cells and granted them increased buffering capacity against iron disorder, protecting them from ferroptosis and favoring drug resistance. However, dihydroartemisinin (DHA) restrained MDR K562/ADM cell viability and enhanced the sensitivity to ADM by strengthening ferroptosis induced by downregulation of GSH levels and GPX4, IRP2, and FTH expression, upregulation of reactive oxygen species (ROS) levels, and the consequent suppression of total serine/threonine kinase (AKT), total mammalian target of rapamycin (t-mTOR), phosphorylated mTOR (p-mTOR), and p-mTOR/t-mTOR levels. Moreover, compared with K562 cells, MDR K562/ADM cells exhibited greater ROS increases, GSH decreases, and viability rescue after ferroptosis inhibitor treatment owing to further suppression of FTH1, GPX4, p-mTOR, and p-mTOR/t-mTOR. Collectively, the increase in oxidative damage and the blockade of antioxidant defence shaped DHA-induced ferroptosis, which was responsible for the sensitivity of MDR leukemia cells to DHA. Regulating iron homeostasis/ROS/AKT/mTOR might be a potential chemotherapeutic strategy for sensitizing drug-resistant leukemia.
铁死亡在肿瘤耐药中的分子机制和作用尚不清楚。在本研究中,我们发现多药耐药(MDR)K562/阿霉素(ADM)白血病细胞比亲本药物敏感的 K562 白血病细胞具有更高的谷胱甘肽(GSH)水平和铁调节蛋白 2(IRP2)、转铁蛋白受体、铁蛋白重链 1(FTH1)和过氧化物酶 4(GPX4)表达。这些升高可能增加了 K562/ADM 细胞的抗氧化能力,并赋予它们对铁紊乱的更强缓冲能力,使它们免受铁死亡并有利于耐药性。然而,二氢青蒿素(DHA)通过下调 GSH 水平和 GPX4、IRP2 和 FTH 表达、上调活性氧(ROS)水平来抑制总丝氨酸/苏氨酸激酶(AKT)、总哺乳动物雷帕霉素靶蛋白(t-mTOR)、磷酸化 mTOR(p-mTOR)和 p-mTOR/t-mTOR,从而抑制 MDR K562/ADM 细胞活力并增强 ADM 的敏感性,从而增强由 GSH 水平和 GPX4 降低引起的铁死亡诱导的耐药 K562/ADM 细胞活力和增强 ADM 的敏感性。此外,与 K562 细胞相比,MDR K562/ADM 细胞在铁死亡抑制剂处理后表现出更大的 ROS 增加、GSH 减少和活力挽救,这是由于进一步抑制 FTH1、GPX4、p-mTOR 和 p-mTOR/t-mTOR 所致。总之,氧化损伤的增加和抗氧化防御的阻断塑造了 DHA 诱导的铁死亡,这是 MDR 白血病细胞对 DHA 敏感的原因。调节铁稳态/ROS/AKT/mTOR 可能是一种潜在的化疗策略,可用于增敏耐药性白血病。