SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11high) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11high cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11high cancers.

中文翻译：

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磷酸戊糖途径依赖性和二硫键应激的胱氨酸转运蛋白调节揭示了癌症中可靶向的代谢脆弱性。

SLC7A11 介导的胱氨酸摄取对于维持氧化还原平衡和细胞存活至关重要。在这里，我们表明这对于具有高水平 SLC7A11 的癌细胞来说是一个巨大的代价。主动导入胱氨酸因其低溶解度而具有潜在毒性，迫使具有高水平 SLC7A11 (SLC7A11high) 的癌细胞组成性地将胱氨酸还原为更易溶解的半胱氨酸。这会显着消耗细胞 NADPH 池，并使此类细胞依赖于戊糖磷酸途径。限制 SLC7A11 高癌细胞的葡萄糖供应会导致细胞内胱氨酸的显着积累、氧化还原系统崩溃和细胞快速死亡，这可以通过防止二硫键积累的治疗来挽救。我们进一步表明葡萄糖转运蛋白抑制剂选择性地杀死 SLC7A11high 癌细胞并抑制 SLC7A11high 肿瘤生长。我们的结果确定了 SLC7A11 相关的胱氨酸代谢和戊糖磷酸途径之间的耦合，并揭示了 SLC7A11 高癌症治疗靶向的伴随代谢脆弱性。