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.
Original language | English (US) |
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Pages (from-to) | 68-74 |
Number of pages | 7 |
Journal | Biochemical and Biophysical Research Communications |
Volume | 606 |
DOIs | |
State | Published - May 28 2022 |
Keywords
- Cyclophosphamide
- Ferroptosis
- GPX4
- Mitochondria
- Parthanatos
ASJC Scopus subject areas
- Biophysics
- Biochemistry
- Molecular Biology
- Cell Biology