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Ferroptosis inhibition by lysosome-dependent catabolism of extracellular protein.
- Source :
-
Cell Chemical Biology . Nov2022, Vol. 29 Issue 11, p1588-1588. 1p. - Publication Year :
- 2022
-
Abstract
- Cancer cells need a steady supply of nutrients to evade cell death and proliferate. Depriving cancer cells of the amino acid cystine can trigger the non-apoptotic cell death process of ferroptosis. Here, we report that cancer cells can evade cystine deprivation-induced ferroptosis by uptake and catabolism of the cysteine-rich extracellular protein albumin. This protective mechanism is enhanced by mTORC1 inhibition and involves albumin degradation in the lysosome, predominantly by cathepsin B (CTSB). CTSB-dependent albumin breakdown followed by export of cystine from the lysosome via the transporter cystinosin fuels the synthesis of glutathione, which suppresses lethal lipid peroxidation. When cancer cells are grown under non-adherent conditions as spheroids, mTORC1 pathway activity is reduced, and albumin supplementation alone affords considerable protection against ferroptosis. These results identify the catabolism of extracellular protein within the lysosome as a mechanism that can inhibit ferroptosis in cancer cells. [Display omitted] • Extracellular albumin can block ferroptosis caused by cystine deprivation • Albumin is cysteine rich and, when catabolized, can replenish GSH stores • Lysosomal albumin catabolism requires cathepsin B (CTSB) • Extracellular albumin suppresses ferroptosis in spheroid cell models Mechanisms that regulate ferroptosis sensitivity and resistance remain poorly defined. Armenta et al. demonstrate that uptake and lysosomal catabolism of extracellular protein can prevent ferroptosis in cystine-deprived cells by maintaining intracellular levels of cysteine and glutathione. This compensatory mechanism may limit the effectiveness of cancer therapies that target cystine uptake. [ABSTRACT FROM AUTHOR]
- Subjects :
- *LYSOSOMES
*CATHEPSIN B
*CATABOLISM
*PROTEINS
*CANCER cells
*AMINO acids
*ALBUMINS
Subjects
Details
- Language :
- English
- ISSN :
- 24519456
- Volume :
- 29
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Cell Chemical Biology
- Publication Type :
- Academic Journal
- Accession number :
- 160213665
- Full Text :
- https://doi.org/10.1016/j.chembiol.2022.10.006