Restricting amino acids from tumours is an emerging therapeutic strategy with substantial promise1. Although typically considered an intracellular antioxidant with tumour-promoting capabilities2, glutathione (GSH), as a tripeptide of cysteine, glutamate and glycine, can be catabolized to release amino acids. The extent to which GSH-derived amino acids are essential to cancers is unclear. Here we show that depletion of intracellular GSH does not alter tumour growth and extracellular GSH is highly abundant in the tumour microenvironment, highlighting the potential importance of GSH outside tumours. Supplementation with GSH rescues cancer cell survival and growth in cystine-deficient conditions, and this rescue depends on the catabolic activity of γ-glutamyltransferases. Finally, pharmacological targeting of the activity of γ-glutamyltransferases prevents the breakdown of circulating GSH, reduces tumour cysteine levels and slows tumour growth. Our findings indicate a non-canonical role for GSH in supporting tumours by acting as a reservoir of amino acids. Depriving tumours of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with cancer. Furthermore, these findings change our view of GSH and how amino acids, including cysteine, are supplied to cells.
限制肿瘤获取氨基酸是一种具有巨大潜力的新兴治疗策略¹。尽管谷胱甘肽通常被视为一种具有促癌能力的细胞内抗氧化剂²，但作为由半胱氨酸、谷氨酸和甘氨酸组成的三肽，它可以通过分解代谢释放氨基酸。目前尚不清楚源自谷胱甘肽的氨基酸对癌症的重要性程度。本研究表明，消耗细胞内谷胱甘肽并不会改变肿瘤生长，而细胞外谷胱甘肽在肿瘤微环境中高度丰富，这凸显了谷胱甘肽在肿瘤外的潜在重要性。在胱氨酸缺乏条件下，补充谷胱甘肽可挽救癌细胞的存活和生长，且这种挽救依赖于γ-谷氨酰转移酶的分解代谢活性。最后，通过药物靶向抑制γ-谷氨酰转移酶的活性，可以阻止循环谷胱甘肽的分解，降低肿瘤半胱氨酸水平，并减缓肿瘤生长。我们的发现揭示了谷胱甘肽通过充当氨基酸储备库来支持肿瘤的非经典作用。剥夺肿瘤的细胞外谷胱甘肽或抑制其分解，可能是一种对癌症患者具有治疗可行性的方法。此外，这些发现改变了我们对谷胱甘肽以及包括半胱氨酸在内的氨基酸如何供给细胞的认识。
Catabolism of extracellular glutathione supplies cysteine to support tumours
肿瘤(癌症)患者之家