Role of ferritinophagy in cystine deprivation-induced cell death in glioblastoma cells

Ferroptosis is a form of cell death caused by iron-dependent lipid peroxidation. Cancer cells increase cystine uptake for the synthesis of glutathione (GSH), which is used by glutathione peroxidase 4 to reduce lipid peroxides. Here, we report that cystine deprivation in glioblastoma cells, but not i...

Full description

Saved in:
Bibliographic Details
Published in:Biochemical and biophysical research communications 2021-02, Vol.539, p.56-63
Main Authors: Hayashima, Kazuki, Kimura, Ikuo, Katoh, Hironori
Format: Article
Language:English
Subjects:
Cell death
Cystine
Ferritin
Glioblastoma
Glutathione
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Ferroptosis is a form of cell death caused by iron-dependent lipid peroxidation. Cancer cells increase cystine uptake for the synthesis of glutathione (GSH), which is used by glutathione peroxidase 4 to reduce lipid peroxides. Here, we report that cystine deprivation in glioblastoma cells, but not inhibition of GSH synthesis by l-buthionine sulfoximine (BSO), induces ferroptosis. We found that cystine deprivation decreased the protein levels of ferritin heavy chain FTH1, whereas it was increased by BSO treatment. The lysosome inhibitor bafilomycin A1 or deletion of nuclear receptor coactivator 4 (NCOA4) inhibited cystine deprivation-induced decrease in FTH1 protein levels and cell death. In addition, cystine deprivation induced microtubule-associated protein light chain 3 (LC3)-II protein accumulation, suggesting that cystine deprivation induces ferritinophagy. BSO causes cell death when glioblastoma cells are treated with iron inducers, ferrous ammonium sulfate or hemin. On the other hand, cystine deprivation-induced degradation of FTH1 and cell death required glutamine. This study suggests that ferritinophagy, in addition to GSH depletion, plays an important role in cystine deprivation-induced ferroptosis in glioblastoma cells. •Cystine deprivation, but not inhibition of glutathione synthesis, induces ferroptosis in glioblastoma cells.•Cystine deprivation, but not inhibition of glutathione synthesis, induces ferritinophagy.•Inhibition of glutathione synthesis causes cell death when glioblastoma cells are treated with iron inducers.•Cystine deprivation-induced degradation of ferritin and cell death require glutamine.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2020.12.075