Li Hao, Zhou Wei, Wei Huiping, Li Longlong, Wang Xu, Li Yongli, Li Shaoshan, Li Changzheng
Department of Surgery, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453003, China.
Department of Histology and Embryology, Sanquan College of Xinxiang Medical University, Xinxiang, Henan 453003, China.
J Oncol. 2021 Dec 7;2021:3015710. doi: 10.1155/2021/3015710. eCollection 2021.
Ferritinophagy is a process of ferritin degradation in lysosomes; however, how its effect on other cellular events, such as epithelial-mesenchymal transition (EMT) and ferroptosis remains elusive. In this study, we determined how ferritinophagic flux influence the status of EMT and ferroptosis in HepG2 cell. Our data revealed that 2-pyridylhydrazone dithiocarbamate s-acetic acid (PdtaA) induced EMT inhibition involved ferritinophagy-mediated ROS production, but addition of ferrostatin-1 could attenuate the effect of PdtaA on the regulation of EMT-related proteins, suggesting that ferroptosis might involve in the EMT regulation. Next, downregulation of Gpx4 and xCT as well as enhanced lipid peroxidation further supported that PdtaA was able to induce ferroptosis. Knockdown of NCOA4 significantly attenuated the regulatory effect of PdtaA on related proteins which highlighted that the strength of ferritinophagic flux (NCOA4/ferritin) was a driving force in determination of the status of EMT and ferroptosis. Furthermore, NDRG1 activation was also observed, and knockdown of NDRG1 similarly influenced the expressions of ferroptosis-related proteins, suggesting that NDRG1 also involved ferroptosis induction, which was first reported. Taken together, PdtaA-induced EMT inhibition, ferroptosis, and NDRG1 activation all depended on the strength of ferritinophagic flux.
铁蛋白自噬是铁蛋白在溶酶体中降解的过程；然而，其对其他细胞事件（如上皮-间质转化（EMT）和铁死亡）的影响仍不清楚。在本研究中，我们确定了铁蛋白自噬通量如何影响HepG2细胞中EMT和铁死亡的状态。我们的数据显示，2-吡啶腙二硫代氨基甲酸盐s-乙酸（PdtaA）诱导的EMT抑制涉及铁蛋白自噬介导的ROS产生，但添加铁死亡抑制剂-1可减弱PdtaA对EMT相关蛋白调控的影响，这表明铁死亡可能参与EMT调控。接下来，Gpx4和xCT的下调以及脂质过氧化的增强进一步支持了PdtaA能够诱导铁死亡。NCOA4的敲低显著减弱了PdtaA对相关蛋白的调控作用，这突出表明铁蛋白自噬通量（NCOA4/铁蛋白）的强度是决定EMT和铁死亡状态的驱动力。此外，还观察到NDRG1的激活，NDRG1的敲低同样影响铁死亡相关蛋白的表达，这表明NDRG1也参与铁死亡诱导，这是首次报道。综上所述，PdtaA诱导的EMT抑制、铁死亡和NDRG1激活均依赖于铁蛋白自噬通量的强度。
