Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair
Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair
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谷氨酰胺合成酶通过促进核苷酸代谢和随后的 DNA 损伤修复来增强抗辐射能力
DOI：
10.1016/j.celrep.2019.07.002
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发表时间：
2019-07-30
期刊：
影响因子：
8.8
通讯作者：
Sun, Lun-Quan
中科院分区：
文献类型：
--
作者：
Fu, Shujun;Li, Zhi;Sun, Lun-Quan
放射抵抗是肿瘤放射治疗中的一个关键问题。辐射主要通过引起DNA损伤来杀死肿瘤细胞。因此，DNA损伤修复效率是限制放射治疗疗效的最重要因素之一。谷氨酰胺的生理功能是产生蛋白质和核苷酸。在这里，我们研究了谷氨酰胺代谢对癌症治疗反应的影响，特别是在辐射诱导的压力下。我们发现，辐射抗性细胞具有低的糖酵解，线粒体呼吸和TCA循环，但高谷氨酰胺拮抗剂。转录组分析表明，谷氨酰胺合成酶（GS）是一种将谷氨酸和氨催化为谷氨酰胺的酶，是导致代谢改变的原因。ChIP和荧光素酶报告基因分析表明，GS可以转录调控STAT5。敲低GS延迟DNA修复，减弱核苷酸代谢，并增强体外和体内的放射敏感性。我们的数据表明GS通过促进核苷酸合成和加速DNA修复将谷氨酰胺代谢与放疗反应联系起来。
Radiation resistance is a critical problem in radiotherapy for cancer. Radiation kills tumor cells mainly through causing DNA damage. Thus, efficiency of DNA damage repair is one of the most important factors that limits radiotherapy efficacy. Glutamine physiologically functions to generate protein and nucleotides. Here, we study the impact of glutamine metabolism on cancer therapeutic responses, in particular under irradiation-induced stress. We show that radiation-resistant cells possessed low glycolysis, mitochondrial respiration, and TCA cycle but high glutamine anabolism. Transcriptome analyses revealed that glutamine synthetase (GS), an enzyme catalyzing glutamate and ammonia to glutamine, was responsible for the metabolic alteration. ChIP and luciferase reporter assays revealed that GS could be transcriptionally regulated by STAT5. Knockdown of GS delayed DNA repair, weakened nucleotide metabolism, and enhanced radiosensitivity both in vitro and in vivo. Our data show that GS links glutamine metabolism to radiotherapy response through fueling nucleotide synthesis and accelerating DNA repair.