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

Fu, Shujun; Li, Zhi; Xiao, Lanbo; Hu, Wenfeng; Zhang, Lu; Xie, Bowen; Zhou, Qin; He, Junyang; Qiu, Yanfang; Wen, Ming; Peng, Yanni; Gao, Jie; Tan, Rong; Deng, Yuezhen; Weng, Liang; Sun, Lun‐Quan

doi:10.1016/j.celrep.2019.07.002

Cited by 109 publications

(87 citation statements)

References 43 publications

(40 reference statements)

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“…Glutamine synthetase (GLUL) expression was also associated with RT-resistance ( Supplementary Fig. 1D), consistent with prior reports 27 . IDH3a, a critical mediator of oxidative ATP production through the TCA cycle, was instead associated with RT-sensitivity ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 91%

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

et al. 2020

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Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.

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Section: Resultssupporting

confidence: 91%

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

et al. 2020

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“…Glutamine synthetase (GLUL) expression was also associated with RT-resistance ( Fig. S1D), consistent with the prior reports 26 .…”

Section: Nucleotide Metabolites Correlate With Rt-resistance In Gbmsupporting

confidence: 91%

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Zhou

Yao

Scott

et al. 2020

Preprint

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Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance, and new strategies that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we found that purine metabolites strongly correlated with radiation resistance. Inhibiting purine, but not pyrimidine, synthesis radiosensitized GBM cells and patient-derived neurospheres by impairing DNA repair in a nucleoside-dependent fashion. Likewise, administration of exogenous purine nucleosides protected sensitive GBM models from radiation by promoting DNA repair. Combining an FDA-approved inhibitor of de novo purine synthesis with radiation arrested growth in GBM xenograft models and depleted intratumoral guanylates. High expression of the rate-limiting enzyme of de novo GTP synthesis was associated with shorter survival in GBM patients. Together, these findings indicate that inhibiting de novo purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.

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“…It has recently been demonstrated that radioresistant cancer cells reprogram metabolic flux toward glutamine anabolism. Under these conditions, cancer cells highly express glutamine synthetase, facilitating cancer cell growth under radiation stress 150 . Moreover, evidence has shown that during the DNA damage response, normal cells show a decrease in glutaminolysis controlled by SIRT4 protein suppressing GLUD1.…”

Section: Glutamine Metabolism Upon Cellular Stressesmentioning

confidence: 99%

Glutamine reliance in cell metabolism

et al. 2020

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As knowledge of cell metabolism has advanced, glutamine has been considered an important amino acid that supplies carbon and nitrogen to fuel biosynthesis. A recent study provided a new perspective on mitochondrial glutamine metabolism, offering mechanistic insights into metabolic adaptation during tumor hypoxia, the emergence of drug resistance, and glutaminolysis-induced metabolic reprogramming and presenting metabolic strategies to target glutamine metabolism in cancer cells. In this review, we introduce the various biosynthetic and bioenergetic roles of glutamine based on the compartmentalization of glutamine metabolism to explain why cells exhibit metabolic reliance on glutamine. Additionally, we examined whether glutamine derivatives contribute to epigenetic regulation associated with tumorigenesis. In addition, in discussing glutamine transporters, we propose a metabolic target for therapeutic intervention in cancer.

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

Abstract: Highlights d Radioresistant cancer cells reprogram metabolic flux toward glutamine anabolism d GS promotes cellular nucleotide synthesis for efficient DNA repair d High expression of GS facilitates growth of cancer cells under radiation stress d GS is transcriptionally regulated by STAT5

Cited by 109 publications

References 43 publications

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Glutamine reliance in cell metabolism

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