![]() In fact, many reports have demonstrated that inhibition or down-regulation of system x c − function attenuates proliferation, invasion, and metastasis of cancer cells in vitro and in vivo 16. In addition, system x c − has recently emerged as a potential target in the context of cancer therapy 15. Since the uptake of cystine and cystathionine is inevitably coupled to the release of glutamate, a major neurotransmitter in the central nervous system, system x c − has been linked to a variety of normal functions and neurological diseases, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis 14. Inhibition of system x c − causes a rapid drop of intracellular glutathione level and cell death in most of cultured cells 13. Some part of cysteine is released via neutral amino acid transporters, thus contributing to maintain extracellular redox balance 10, and a cystine/cysteine redox cycle which can act independently of cellular GSH 11, 12. Cystine taken up via system x c − is rapidly reduced to cysteine, which is used for synthesis of protein and glutathione (GSH) 9, the major endogenous antioxidant in mammalian cells. Recently, we have demonstrated that cystathionine is also a physiological substrate, which can be exchanged with glutamate, and that system x c − plays an essential role for maintaining cystathionine in immune tissues like thymus and spleen 8. System x c − exchanges intracellular glutamate with extracellular cystine at a 1:1 molar ratio 7. xCT was shown to be responsible for the specific function of system x c −, whereas 4F2 heavy chain, which had been known as one of surface antigens (CD98), is the common subunit of some other amino acid transporters 4, 5, 6. This transporter is composed of xCT (SLC7A11), which is the substrate-specific subunit 2, 3, and 4F2 heavy chain (SLC3A2). ![]() System x c − is one among many amino acid transporters expressed in the plasma membrane of mammalian cells 1. Hence, our data suggests that only a very short pre-treatment of erastin suffices to synergize with cisplatin to efficiently induce cancer cell death, findings that might guide us in the design of novel cancer treatment paradigms. More importantly, short exposure of tumor cells with erastin strongly potentiated the cytotoxic effects of cisplatin to efficiently eradicate tumor cells. These inhibitory effects towards system x c − did not involve cysteine modifications of the transporter. Notably, only a very short exposure of cells with low erastin concentrations was sufficient to cause a strong and persistent inhibition of system x c −, causing glutathione depletion. ![]() When comparing with some well-known inhibitors of system x c −, erastin was the most efficient inhibitor acting at low micromolar concentrations. Therefore, we sought to interrogate in more detail the underlying mechanism of erastin’s pro-ferroptotic effects. Although the inhibitory effect of erastin towards system x c − is well-documented, nothing is known about its mechanism of action. In this context, the small molecule erastin was reported to target and inhibit system x c −, leading to cysteine starvation, glutathione depletion and consequently ferroptotic cell death. System x c − was recently described as the most upstream node in a novel form of regulated necrotic cell death, called ferroptosis.
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