合成谷胱甘肽(GSH)需要半胱氨酸,辅酶A,其他含硫代谢物,大多数蛋白质。在大多数细胞中,半胱氨酸来自细胞外二硫键来源,包括胱氨酸,谷胱甘肽-二硫化物,和肽。硫氧还蛋白还原酶-1(TrxR1)-或谷胱甘肽-二硫化物还原酶(GSR)驱动的酶系统可以通过硫氧还蛋白促进胱氨酸还原,谷氧还蛋白,或其他硫氧还蛋白折叠蛋白。游离胱氨酸通过胱氨酸-谷氨酸反转运蛋白进入细胞,xCT,但系统性地,血浆谷胱甘肽-二硫化物可能作为胱氨酸来源占主导地位。Erastin,同时抑制xCT和电压依赖性阴离子通道,诱导铁细胞死亡,之所以如此命名,是因为这种类型的细胞死亡被铁螯合剂拮抗。许多癌细胞似乎倾向于铁性凋亡,这已被提议作为一个有针对性的癌症责任。铁凋亡与脂质过氧化和谷胱甘肽过氧化物酶4(GPX4)或铁凋亡抑制蛋白1(FSP1)的损失有关,它们都能防止脂质过氧化物的积累。已经提出,xCT抑制诱导的细胞半胱氨酸缺乏降低GSH水平,饥饿GPX4以减少功率并允许膜脂质过氧化物积累,从而导致铁中毒。然而,铁中毒的各个方面还没有完全理解,需要进一步审查,例如,既不破坏GSH合成,GSH的损失,也不破坏谷胱甘肽二硫化物还原酶(GSR),在动物模型中引发铁中毒。在这里,我们重新评估Erastin之间的关系,xCT,GPX4,细胞半胱氨酸和GSH,RSL3或ML162,和铁凋亡。我们的结论是,而Cys和铁蛋白都是癌症的潜在负担,他们彼此之间的关系仍然没有得到足够的理解。
Cysteine is required for synthesis of glutathione (GSH), coenzyme A, other sulfur-containing metabolites, and most proteins. In most cells, cysteine comes from extracellular disulfide sources including cystine, glutathione-disulfide, and peptides. The thioredoxin reductase-1 (TrxR1)- or glutathione-disulfide reductase (GSR)-driven enzymatic systems can fuel cystine reduction via thioredoxins, glutaredoxins, or other thioredoxin-fold proteins. Free cystine enters cells thorough the cystine-glutamate antiporter, xCT, but systemically, plasma glutathione-disulfide might predominate as a cystine source. Erastin, inhibiting both xCT and voltage-dependent anion channels, induces ferroptotic cell death, so named because this type of cell death is antagonized by iron-chelators. Many cancer cells seem to be predisposed to ferroptosis, which has been proposed as a targetable cancer liability. Ferroptosis is associated with lipid peroxidation and loss of either glutathione peroxidase-4 (GPX4) or ferroptosis suppressor protein-1 (FSP1), which each prevent accumulation of lipid peroxides. It has been suggested that an xCT inhibition-induced cellular cysteine-deficiency lowers GSH levels, starving GPX4 for reducing power and allowing membrane lipid peroxides to accumulate, thereby causing ferroptosis. Aspects of ferroptosis are however not fully understood and need to be further scrutinized, for example that neither disruption of GSH synthesis, loss of GSH, nor disruption of glutathione disulfide reductase (GSR), triggers ferroptosis in animal models. Here we reevaluate the relationships between Erastin, xCT, GPX4, cellular cysteine and GSH, RSL3 or ML162, and ferroptosis. We conclude that, whereas both Cys and ferroptosis are potential liabilities in cancer, their relationship to each other remains insufficiently understood.