Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair

doi:10.1016/j.celrep.2019.07.002

. 2019 Jul 30;28(5):1136-1143.e4.

doi: 10.1016/j.celrep.2019.07.002.

Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair

Shujun Fu¹, Zhi Li², Lanbo Xiao³, Wenfeng Hu¹, Lu Zhang¹, Bowen Xie¹, Qin Zhou⁴, Junju He⁵, Yanfang Qiu⁵, Ming Wen¹, Yanni Peng⁵, Jie Gao⁵, Rong Tan², Yuezhen Deng², Liang Weng², Lun-Quan Sun⁶

Affiliations

¹ Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China.
² 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.
³ Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410008, China.
⁴ Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China.
⁵ Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
⁶ 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. Electronic address: lunquansun@csu.edu.cn.

PMID: 31365859
DOI: 10.1016/j.celrep.2019.07.002

Free article

Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair

Shujun Fu et al. Cell Rep. 2019.

Free article

. 2019 Jul 30;28(5):1136-1143.e4.

doi: 10.1016/j.celrep.2019.07.002.

Authors

Affiliations

¹ Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China.
² 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.
³ Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410008, China.
⁴ Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China.
⁵ Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
⁶ 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. Electronic address: lunquansun@csu.edu.cn.

PMID: 31365859
DOI: 10.1016/j.celrep.2019.07.002

Abstract

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.

Keywords: DNA damage repair; glutamine synthetase; radiation resistance.

PubMed Disclaimer

Cited by

Linking Serine/Glycine Metabolism to Radiotherapy Resistance.
Sánchez-Castillo A, Vooijs M, Kampen KR. Sánchez-Castillo A, et al. Cancers (Basel). 2021 Mar 10;13(6):1191. doi: 10.3390/cancers13061191. Cancers (Basel). 2021. PMID: 33801846 Free PMC article. Review.
BCAT1 promotes lung adenocarcinoma progression through enhanced mitochondrial function and NF-κB pathway activation.
Yu M, Zhao Q, Li J, Xu F, Zhang Z, Liu Y, Dai L, Zhang B, Zhang J, Zhang J. Yu M, et al. J Zhejiang Univ Sci B. 2022 Sept 15;23(9):760-769. doi: 10.1631/jzus.B2100985. J Zhejiang Univ Sci B. 2022. PMID: 36111572 Free PMC article.
Small Molecule Signatures of Mice Lacking T-cell p38 Alternate Activation, a Model for Immunosuppression Conditions, after Total-Body Irradiation.
Pannkuk EL, Laiakis EC, Angdisen J, Jayatilake MM, Ake P, Lin LY, Li HH, Fornace AJ. Pannkuk EL, et al. Radiat Res. 2022 Jun 1;197(6):613-625. doi: 10.1667/RADE-21-00199.1. Radiat Res. 2022. PMID: 35245386 Free PMC article.
STAT proteins in cancer: orchestration of metabolism.
Li YJ, Zhang C, Martincuks A, Herrmann A, Yu H. Li YJ, et al. Nat Rev Cancer. 2023 Mar;23(3):115-134. doi: 10.1038/s41568-022-00537-3. Epub 2023 Jan 3. Nat Rev Cancer. 2023. PMID: 36596870 Review.
Resistance of Hypoxic Cells to Ionizing Radiation Is Mediated in Part via Hypoxia-Induced Quiescence.
Menegakis A, Klompmaker R, Vennin C, Arbusà A, Damen M, van den Broek B, Zips D, van Rheenen J, Krenning L, Medema RH. Menegakis A, et al. Cells. 2021 Mar 10;10(3):610. doi: 10.3390/cells10030610. Cells. 2021. PMID: 33801903 Free PMC article.

See all "Cited by" articles

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair

Affiliations

Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair

Authors

Affiliations

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Miscellaneous

Abstract

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Miscellaneous