下调和上调
ESCRT公司
细胞生物学
程序性细胞死亡
化学
癌细胞
辅酶Q10
线粒体
生物化学
细胞凋亡
泛醇
GPX4
癌症研究
生物
内体
癌症
细胞内
氧化应激
基因
超氧化物歧化酶
细胞色素c
遗传学
谷胱甘肽过氧化物酶
辅酶Q-细胞色素c还原酶
作者
Enyong Dai,Wenlong Zhang,Dalong Cong,Rui Kang,Jing Wang,Daolin Tang
标识
DOI:10.1016/j.bbrc.2020.01.066
摘要
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.
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