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首页> 外文期刊>Cell biology international. >The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin
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The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin

机译：通过损害Dat 3 / NRF2 / GPX4信号传导诱导恶性凋亡，增强了骨肉瘤细胞对顺铂的敏感性

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Abstract Recent studies have indicated that promoting ferroptosis is a promising approach to attenuate drug resistance of cancer cells. Hence, this study aimed to induce ferroptosis in osteosarcoma cells, thereby increasing the sensitivity to cisplatin. Osteosarcoma cells MG63 and Saos‐2 were incubated with increasing doses of cisplatin to generate cisplatin‐resistant strains, MG63/DDP and Saos‐2/DDP. 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) and flow cytometry assays were performed to evaluate cell proliferation and cell death, respectively. Malondialdehyde (MDA), reactive oxygen species (ROS), and lipid oxidation in cells were measured to evaluate the degree of cell ferroptosis. MG63/DDP and Saos‐2/DDP cells showed increased viability and decreased death rate compared with MG63 and Saos‐2 cells, respectively, upon cisplatin treatment. Western blotting analysis indicated that protein levels of p‐STAT3 (Ser727), nuclear factor erythroid 2‐related factor 2 (Nrf2), and glutathione peroxidase 4 (GPx4) in drug‐resistant strains increased significantly in response to cisplatin. Co‐treatment with cisplatin and agonists of ferroptosis, Erastin, and RSL3, remarkably increased MDA, ROS, lipid oxidation, and sensitivity to cisplatin, in MG63/DDP and Saos‐2/DDP cells. Similar results were observed by co‐treatment of cells with cisplatin and a STAT3 inhibitor. The reduction of protein levels of p‐STAT3 (Ser727), Nrf2, and GPx4 in MG63/DDP and Saos‐2/DDP cells resulted in increased ferroptosis and sensitivity to cisplatin. These results indicate that cisplatin‐resistant osteosarcoma cells inhibited ferroptosis after exposure to low doses of cisplatin. However, ferroptosis agonists and STAT3 inhibitor reactivated ferroptosis in the cells and consequently increased sensitivity to cisplatin. This study demonstrates a new approach to attenuate resistance of osteosarcoma to cisplatin in vitro .
机译：摘要最近的研究表明，促进脱裂病变是衰减癌细胞耐药性的有希望的方法。因此，本研究旨在诱导骨肉瘤细胞中的裂解组织，从而增加对顺铂的敏感性。将骨肉瘤细胞Mg63和Saos-2加入含量的顺铂，以产生顺铂抗性菌株，Mg63 / DDP和Saos-2 / DDP。进行3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴铵（MTT）和流式细胞术测定，分别评估细胞增殖和细胞死亡。测定丙二醛（MDA），反应性氧物质（ROS）和细胞中的脂质氧化以评估细胞脱裂剂程度。 Mg63 / DDP和SAOS-2 / DDP细胞分别在顺铂治疗时分别与MG63和SAOS-2细胞相比增加了活力和死亡率下降。 Western印迹分析表明，抗药物抗性菌株中P-STAT3（SER727），核因子红外血管素2相关因子2（NRF2）和谷胱甘肽过氧化物酶4（GPX4）的蛋白质水平显着增加。用Cisplatin和Cisplatin的激酶和激动剂的共同治疗，显着增加MDA，ROS，脂氧化和对顺铂，Mg63 / DDP和Saos-2 / DDP细胞的敏感性。通过使用顺铂和STAT3抑制剂的细胞共处理来观察到类似的结果。在Mg63 / DDP和SAOS-2 / DDP细胞中降低P-STAT3（SER727），NRF2和GPX4中的蛋白质水平导致裂解蛋白酶凋亡增加和对顺铂的敏感性增加。这些结果表明，在暴露于低剂量的顺铂后，顺铂抗性骨肉瘤细胞抑制了恶性腺炎。然而，脱裂剂激动剂和STAT3抑制剂在细胞中重新激活了硬化，因此对顺铂的敏感性增加了。该研究表明，一种新方法，可以在体外衰减骨肉瘤抗性胰岛素。

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