Ferroptosis Inhibition by Lysosome-Dependent Catabolism of Extracellular Protein

This dataset contains original uncropped western blots, an ImageJ macro, and an R program, related to this work whose abstract is as follows: Cancer cells must ensure a steady supply of nutrients to enable proliferation and evade cell death. 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 the 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. Notably, 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.