铁死亡通过溶酶体依赖的细胞外蛋白分解代谢抑制。
Ferroptosis inhibition by lysosome-dependent catabolism of extracellular protein.
机构信息
Department of Biology, Stanford University, Stanford, CA 94305, USA.
Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; The Institute for Chemistry, Engineering, & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA.
出版信息
Cell Chem Biol. 2022 Nov 17;29(11):1588-1600.e7. doi: 10.1016/j.chembiol.2022.10.006. Epub 2022 Oct 27.
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.
癌细胞需要稳定的营养供应来逃避细胞死亡并增殖。剥夺癌细胞胱氨酸会触发非凋亡性细胞死亡过程中的铁死亡。在这里，我们报告说，癌细胞可以通过摄取和分解富含半胱氨酸的细胞外蛋白白蛋白来逃避胱氨酸剥夺诱导的铁死亡。这种保护机制通过 mTORC1 抑制得到增强，涉及溶酶体中白蛋白的降解，主要由组织蛋白酶 B（CTSB）介导。CTSB 依赖性白蛋白分解，随后胱氨酸通过转运蛋白胱氨酸转运蛋白从溶酶体中输出，为谷胱甘肽的合成提供燃料，谷胱甘肽抑制致命的脂质过氧化。当癌细胞在作为球体的非贴壁条件下生长时，mTORC1 途径的活性降低，单独补充白蛋白就能提供对铁死亡的显著保护。这些结果表明，溶酶体内细胞外蛋白的分解是一种可以抑制癌细胞铁死亡的机制。
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