Department of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
The Second Clinical Medical School of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China; Department of Wangjiangshan, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
Redox Biol. 2020 May;32:101483. doi: 10.1016/j.redox.2020.101483. Epub 2020 Mar 2.
Ferroptosis is a newly discovered form of non-apoptotic regulated cell death and is characterized by iron-dependent and lipid peroxidation. Due to the enhanced dependence on iron in cancer cells, induction of ferroptosis is becoming a promising therapeutic strategy. However, the precise underlying molecular mechanism and regulation process of ferroptosis remains largely unknown. In the present study, we demonstrate that the protein Frataxin (FXN) is a key regulator of ferroptosis by modulating iron homeostasis and mitochondrial function. Suppression of FXN expression specifically repressed the proliferation, destroyed mitochondrial morphology, impeded Fe-S cluster assembly and activated iron starvation stress. Moreover, suppression of FXN expression significantly enhanced erastin-induced cell death through accelerating free iron accumulation, lipid peroxidation and resulted in dramatic mitochondria morphological damage including enhanced fragmentation and vanished cristae. In addition, this type of cell death was confirmed to be ferroptosis, since it could be pharmacologically restored by ferroptotic inhibitor Fer-1 or GSH, but not by inhibitors of apoptosis, necrosis. Vice versa, enforced expression of FXN blocked iron starvation response and erastin-induced ferroptosis. More importantly, pharmacological or genetic blocking the signal of iron starvation could completely restore the resistance to ferroptosis in FXN knockdown cells and xenograft graft in vivo. This paper suggests that FXN is a novel ferroptosis modulator, as well as a potential provided target to improve the antitumor activity based on ferroptosis.
铁死亡是一种新发现的非凋亡性细胞死亡形式，其特征为铁依赖性和脂质过氧化。由于癌细胞对铁的依赖性增强，诱导铁死亡正成为一种有前途的治疗策略。然而，铁死亡的确切潜在分子机制和调控过程在很大程度上仍然未知。在本研究中，我们证明了 Frataxin（FXN）蛋白通过调节铁平衡和线粒体功能，是铁死亡的关键调节因子。FXN 表达的抑制特异性地抑制了增殖，破坏了线粒体形态，阻碍了 Fe-S 簇的组装，并激活了铁饥饿应激。此外，抑制 FXN 表达显著增强了依拉司琼诱导的细胞死亡，通过加速游离铁的积累、脂质过氧化，导致线粒体形态的显著损伤，包括增强的碎片化和嵴的消失。此外，这种细胞死亡被证实为铁死亡，因为它可以通过铁死亡抑制剂 Fer-1 或 GSH 进行药理学恢复，但不能通过凋亡、坏死抑制剂进行恢复。相反，FXN 的强制表达阻断了铁饥饿反应和依拉司琼诱导的铁死亡。更重要的是，药理学或遗传阻断铁饥饿信号可以完全恢复 FXN 敲低细胞对铁死亡的抗性，以及体内异种移植移植。本文表明，FXN 是一种新型的铁死亡调节剂，也是提高基于铁死亡的抗肿瘤活性的潜在靶点。
