Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair
Shujun Fu,
Zhi Li,
Lanbo Xiao,
Wenfeng Hu,
Lu Zhang,
Bowen Xie,
Qin Zhou,
Junju He,
Yanfang Qiu,
Ming Wen,
Yanni Peng,
Jie Gao,
Rong Tan,
Yuezhen Deng,
Liang Weng,
Lun-Quan Sun
Affiliations
Shujun Fu
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China
Zhi Li
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, China
Lanbo Xiao
Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410008, China
Wenfeng Hu
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China
Lu Zhang
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China
Bowen Xie
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China
Qin Zhou
Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China
Junju He
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
Yanfang Qiu
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
Ming Wen
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China
Yanni Peng
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
Jie Gao
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
Rong Tan
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, China
Yuezhen Deng
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, China
Liang Weng
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, China
Lun-Quan Sun
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, China; National Clinical Research Center for Gerontology, Changsha 410008, China; Corresponding author
Summary: 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. : Radiation resistance is one of the limiting factors for therapeutic efficacy and results in cancer recurrence. Fu et al. identify GS as a switch that drives cellular metabolic flux toward nucleotide synthesis for efficient DNA repair and thus leads to radiation resistance of cancer cells. Keywords: glutamine synthetase, radiation resistance, DNA damage repair
