Cyclophosphamide-induced GPX4 degradation triggers parthanatos by activating AIFM1.
Biochem Biophys Res Commun
; 606: 68-74, 2022 05 28.
Article
in En
| MEDLINE
| ID: mdl-35339754
ABSTRACT
Cyclophosphamide is an alkylating agent used to treat a variety of cancers, including leukemia. Here, we show a previously unrecognized role of cyclophosphamide in triggering the protein degradation of glutathione peroxidase 4 (GPX4), a phospholipid hydroperoxidase that protects cells from oxidative damage. Mechanistically, we found that the ubiquitin-proteasome system, but not autophagy, mediates cyclophosphamide-induced degradation of GPX4 in human leukemia cell lines. Surprisingly, cyclophosphamide-induced degradation of GPX4 leads to caspase-independent parthanatos, but not lipid peroxidation-mediated ferroptosis, through the nuclear translocation of apoptosis-inducing factor mitochondria-associated 1 (AIFM1). Consequently, the overexpression of GPX4 or the knockdown of AIFM1 limits the anticancer activity of cyclophosphamide in vitro and in xenograft tumor models. These findings establish a new framework for understanding the central role of GPX4 in blocking oxidative cell death.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leukemia
/
Apoptosis Inducing Factor
/
Ferroptosis
/
Parthanatos
/
Phospholipid Hydroperoxide Glutathione Peroxidase
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Biochem Biophys Res Commun
Year:
2022
Document type:
Article
Affiliation country:
China