Dysregulated Glutamate Transporter SLC1A1 Propels Cystine Uptake via Xc- for Glutathione Synthesis in Lung Cancer
Dysregulated Glutamate Transporter SLC1A1 Propels Cystine Uptake via Xc- for Glutathione Synthesis in Lung Cancer
复制标题
失调的谷氨酸转运蛋白 SLC1A1 通过 Xc(-) 促进胱氨酸摄取，以促进肺癌中的谷胱甘肽合成。
DOI：
10.1158/0008-5472.can-20-0617
复制
发表时间：
2021-02-01
期刊：
影响因子：
11.2
通讯作者：
Deng, Jiong
中科院分区：
文献类型：
--
作者：
Guo, Wenzheng;Li, Kaimi;Deng, Jiong
癌细胞需要产生大量的谷胱甘肽（GSH）来缓冲肿瘤发展过程中的氧化应激。GSH生物合成的限速步骤是通过胱氨酸/谷氨酸反向转运体Xc（-）摄取胱氨酸。XC（-）是一种钠非依赖性反向转运蛋白，由细胞外胱氨酸和细胞内谷氨酸跨细胞膜的浓度梯度被动驱动。在癌细胞中通过Xc（-）增加胱氨酸的摄取增加细胞外谷氨酸的水平，其随后将抑制通过Xc（-）的胱氨酸摄取。因此，癌细胞必须进化出一种机制来克服这种负反馈调节。在这项研究中，我们报告说，谷氨酸转运蛋白，特别是SLC 1A 1，是紧密交织在一起的胱氨酸摄取和谷胱甘肽的生物合成在肺癌细胞。调控异常的SLC 1A 1是一种钠依赖性谷氨酸载体，它积极地将细胞外谷氨酸再循环到细胞中，通过稳定同位素辅助代谢组学测量，这增强了通过Xc（-）和GSH生物合成的胱氨酸摄取效率。相反，谷氨酸转运体SLC 1A 1的耗竭增加细胞外谷氨酸，这抑制胱氨酸摄取，阻断GSH合成，并诱导氧化应激介导的细胞死亡或生长抑制。此外，谷氨酸转运蛋白在非小细胞肺癌患者的组织样本中经常上调。总之，通过SLC 1A 1的谷氨酸的主动摄取促进了通过Xc（-）的胱氨酸摄取，用于肺肿瘤发生中的GSH生物合成。意义：癌细胞中的细胞GSH不仅由上调的Xc（-）决定，还由失调的谷氨酸转运蛋白决定，这为治疗干预提供了额外的靶点。
Cancer cells need to generate large amounts of glutathione (GSH) to buffer oxidative stress during tumor development. A ratelimiting step for GSH biosynthesis is cystine uptake via a cystine/ glutamate antiporter Xc(-). Xc(-) is a sodium-independent antiporter passively driven by concentration gradients from extracellular cystine and intracellular glutamate across the cell membrane. Increased uptake of cystine via Xc(-) in cancer cells increases the level of extracellular glutamate, which would subsequently restrain cystine uptake via Xc(-). Cancer cells must therefore evolve a mechanism to overcome this negative feedback regulation. In this study, we report that glutamate transporters, in particular SLC1A1, are tightly intertwined with cystine uptake and GSH biosynthesis in lung cancer cells. Dysregulated SLC1A1, a sodium-dependent glutamate carrier, actively recycled extracellular glutamate into cells, which enhanced the efficiency of cystine uptake via Xc(-) and GSH biosynthesis as measured by stable isotope-assisted metabolomics. Conversely, depletion of glutamate transporter SLC1A1 increased extracellular glutamate, which inhibited cystine uptake, blocked GSH synthesis, and induced oxidative stress-mediated cell death or growth inhibition. Moreover, glutamate transporters were frequently upregulated in tissue samples of patients with non-small cell lung cancer. Taken together, active uptake of glutamate via SLC1A1 propels cystine uptake via Xc(-) for GSH biosynthesis in lung tumorigenesis.Significance: Cellular GSH in cancer cells is not only determined by upregulated Xc(-) but also by dysregulated glutamate transporters, which provide additional targets for therapeutic intervention.