Wang Lingjuan, Ouyang Sijin, Li Bin, Wu Hao, Wang Fengli
Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
Tianjin Medical University General Hospital, 300211, Tianjin, China.
Cell Death Discov. 2021 Nov 3;7(1):334. doi: 10.1038/s41420-021-00726-3.
Ferroptosis is a newly characterized form of non-apoptotic-programmed cell death, which is driven by the lethal accumulation of iron-catalyzed lipid peroxides. Uncontrolled ferroptosis is implicated in the pathogenesis of a group of human diseases, while targeted induction of ferroptosis provides a potent therapeutic design for cancers. During the past decade, the fundamental regulatory circuits of ferroptosis have been identified. In this study, we show that the multifaceted Ser/Thr protein kinase GSK-3β acts as a positive modulator of the ferroptosis program. Pharmacological inhibition of GSK-3β by selective inhibitor LY2090314 or genetic KD of GSK-3β by shRNA potently promotes ferroptotic resistance. GSK-3β KD antagonizes the expression of iron metabolic components including DMT1, FTH1, and FTL, leading to the disruption of iron homeostasis and decline in intracellular labile free iron level. Taken together, our findings elaborate an indispensable role of GSK-3β in determining ferroptotic sensitivity by dominating cellular iron metabolism, which provides further insight into GSK-3β as a target for cancer chemotherapy.
铁死亡是一种新发现的非凋亡程序性细胞死亡形式，由铁催化的脂质过氧化物的致死性积累所驱动。不受控制的铁死亡与一组人类疾病的发病机制有关，而靶向诱导铁死亡为癌症提供了一种有效的治疗策略。在过去十年中，铁死亡的基本调控机制已被确定。在本研究中，我们表明多面性的丝氨酸/苏氨酸蛋白激酶GSK-3β作为铁死亡程序的正向调节因子发挥作用。选择性抑制剂LY2090314对GSK-3β的药理学抑制或shRNA对GSK-3β的基因敲低均能有效促进铁死亡抗性。GSK-3β基因敲低拮抗包括DMT1、FTH1和FTL在内的铁代谢成分的表达，导致铁稳态破坏和细胞内不稳定游离铁水平下降。综上所述，我们的研究结果阐述了GSK-3β在通过主导细胞铁代谢来决定铁死亡敏感性方面的不可或缺的作用，这为将GSK-3β作为癌症化疗靶点提供了进一步的见解。
