Cyclophosphamide-induced GPX4 degradation triggers parthanatos by activating AIFM1

Liying Liu, Bingju Liu, Guotao Guan, Rui Kang, Yunpeng Dai, Daolin Tang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish (US)
Pages (from-to)68-74
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume606
DOIs
StatePublished - May 28 2022

Keywords

  • Cyclophosphamide
  • Ferroptosis
  • GPX4
  • Mitochondria
  • Parthanatos

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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