Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 523, Issue 4, Pages 966-971Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2020.01.066
Keywords
Ferroptosis; AIFM2; ESCRT; Ubiquinol; CoQ10; Lipid peroxidation
Categories
Funding
- American Cancer Society [RSG-16-014-01-CDD]
- Natural Science Foundation of Jilin Province of China [20160101062JC]
- Health Foundation of the Finance Department of Jilin Province [sczsy201516]
- National Natural Science Foundation of China [30870355, 81370497]
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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.
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