AIFM2 blocks ferroptosis independent of ubiquinol metabolism
AIFM2 blocks ferroptosis independent of ubiquinol metabolism
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DOI：
10.1016/j.bbrc.2020.01.066
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发表时间：
2020-03-19
影响因子：
3.1
通讯作者：
Tang, Daolin
中科院分区：
文献类型：
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作者：
Dai, Enyong;Zhang, Wenlong;Tang, Daolin
铁凋亡是一种多步骤调节的细胞死亡，其特征是过量的铁积累和脂质过氧化。癌细胞可以通过上调抗铁蛋白或下调促铁蛋白来获得对铁凋亡的抗性。凋亡诱导因子α相关2（AIFM 2，也称为FSP 1或PRG 3）最近已被证明是一种内源性铁凋亡抑制剂，但其机制仍不清楚。在这里，我们表明，AIFM 2块erastin，索拉非尼，和RSL 3诱导的ferroptotic癌细胞死亡通过一种机制，独立于泛醇，还原和活性的抗氧化剂形式的辅酶Q10。相比之下，AIFM 2依赖性内体分选复合物所需的运输（ESCRT）-III招聘质膜是负责通过激活膜修复机制，调节膜出芽和分裂的铁凋亡抗性。重要的是，AIFM 2依赖性ESCRT-III途径的遗传抑制增加了索拉非尼在异种移植肿瘤小鼠模型中的抗癌活性。这些发现为肿瘤治疗过程中铁凋亡抵抗的机制提供了新的线索。(C)2020爱思唯尔公司All rights reserved.
Ferroptosis is a multi-step regulated cell death that is characterized by excessive iron accumulation and lipid peroxidation. Cancer cells can acquire resistance to ferroptosis by the upregulation of anti-ferroptotic proteins or by the downregulation of pro-ferroptotic proteins. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1 or PRG3) has been recently demonstrated as an endogenous ferroptosis suppressor, but its mechanism remains obscure. Here, we show that AIFM2 blocks erastin-, sorafenib-, and RSL3-induced ferroptotic cancer cell death through a mechanism independent of ubiquinol, the reduced and active antioxidant form of coenzyme Q10. In contrast, AIFM2-dependent endosomal sorting complexes required for transport (ESCRT)-III recruitment in the plasma membrane is responsible for ferroptosis resistance through the activation of a membrane repair mechanism that regulates membrane budding and fission. Importantly, the genetic inhibition of the AIFM2-dependent ESCRT-III pathway increases the anticancer activity of sorafenib in a xenograft tumor mouse model. These findings shed new light on the mechanism involved in ferroptosis resistance during tumor therapy. (C) 2020 Elsevier Inc. All rights reserved.