Glutamine drives glutathione synthesis and contributes to radiation sensitivity of A549 and H460 lung cancer cell lines
Open accessAbstract
Background Increased glutamine uptake is known to drive cancer cell proliferation, making tumor cells glutamine-dependent. Glutamine provides additional carbon and nitrogen sources for cell growth. The first step in glutamine utilization is its conversion to glutamate by glutaminase (GLS). Glutamate is a precursor for glutathione synthesis, and we investigated the hypothesis that glutamine drives glutathione synthesis and thereby contributes to cellular defense systems.Methods The importance of glutamine for glutathione synthesis was studied in H460 and A549 lung cancer cell lines using glutamine-free medium and bis-2-(5-phenyl-acetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) a GLS inhibitor. Metabolic activities were determined by targeted mass spectrometry.Results A significant correlation between glutamine consumption and glutathione excretion was demonstrated in H460 and A549 tumor cells. Culturing in the presence of [(13)C5]glutamine demonstrated that by 12h >50% of excreted glutathione was derived from glutamine. Culturing in glutamine-free medium or treatment with BPTES, a GLS-specific inhibitor, reduced cell proliferation and viability and abolished glutathione excretion. Treatment with glutathione-ester prevented BPTES-induced cytotoxicity. Inhibition of GLS markedly radiosensitized the lung tumor cell lines, suggesting an important role of glutamine-derived glutathione in determining radiation sensitivity.Conclusions We demonstrate here for the first time that a significant amount of extracellular glutathione is directly derived from glutamine. This finding adds yet another important function to the already known glutamine dependence of tumor cells and probably tumors as well.General significance Glutamine is essential for synthesis and excretion of glutathione to promote cell growth and viability.
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Glutamine is the rate-limiting factor in glutathione synthesis.
“Glutamine is considered the rate-limiting factor in glutathione synthesis58,59.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [59]
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Gong, T., Zheng, C., Ou, X., Zheng, J., Yu, J., Chen, S., Duan, Y., & Liu, W. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.994672 · Cited by 43 · see citing works
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Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis
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“As glutamine 28,61 is essential for the production of ferroptosis protector GSH 62,63 , we depleted glutamine from the culture medium of MM cells and observed that higher levels of lipid ROS were induced in MM cells (Supplementary Fig.”
Papandreou, C., Hernández‐Alonso, P., Bulló, M., Ruiz‐Canela, M., Li, J., Guasch‐Ferré, M., Toledo, E., Clish, C. B., Corella, D., Estruch, R., et al. (2020) · Journal of Nutrition · doi:10.1093/jn/nxaa273 · Cited by 40 · see citing works
“Because glutathione is directly produced from glutamine (50), disruption of the glutamate-glutamine cycle may decrease glutathione stores in the cardiomyocytes, thus increasing their susceptibility to damage from reactive oxygen species.”
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Metabolic Signaling Cascades Prompted by Glutaminolysis in Cancer
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“Byproducts of the “glutaminase” reaction are used for synthesis of purines, pyrimidines, NAD+ cofactors, amino-sugars, glutathione, and non-essential amino acids (NEAA), such as alanine, asparagine, and phosphoserine [45,46,52].”
BackgroundGlutamine promotes escape from therapy-induced senescence in tumor cells
Pacifico, F., Badolati, N., Mellone, S., Stornaiuolo, M., Leonardi, A., & Crescenzi, E. (2021) · Aging · doi:10.18632/aging.203495 · Cited by 36 · see citing works
“Glutamine-derived glutamate also contributes to the biosynthesis of NEAA and glutathione, thus supporting cellular antioxidant defenses [68].”
Metabolic response to radiation therapy in cancer
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“48 Intracellular glutamate is exported out of the cells through the amino acid transport system x c (cid:1) coupled to the in fl ux of extracellular cystine, which serves as a precursor for GSH synthesis.”
BackgroundMetabolomic studies in tissues of mice treated with amifostine and exposed to gamma-radiation
Cheema, A. K., Li, Y., Girgis, M. J., Jayatilake, M. M., Simas, M., Wise, S. Y., Olabisi, A. O., Seed, T. M., & Singh, V. K. (2019) · Scientific Reports · doi:10.1038/s41598-019-52120-w · Cited by 34 · see citing works
The Glutathione Conundrum: Stoichiometric Disconnect between Its Formation and Oxidative Stress
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“Another amino acid, glutamine, that was associated with a decreased risk of MetS in both cohorts has additionally been shown to drive production of glutathione [63].”
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“In glutathione metabolism, glutamine provides additional carbon and nitrogen for cell growth [62], thereby driving glutathione synthesis, and contributes to radiation sensitivity in lung cancer cell lines [62].”
BackgroundEmerging strategies to target cancer metabolism and improve radiation therapy outcomes
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“In addition to glucose, glutamine has also been identified as a possible source of synthesis of glutathione, an ROS scavenger that helps inhibit radiosensitivity.(26) We plan to extend our studies to include earlier time points, beginning immediately (within minutes) after radiation and determine the specific pathways…”
BackgroundSelf-citationJonsson, E. L., Erngren, I., Engskog, M. K. R., Haglöf, J., Arvidsson, T., Hedeland, M., Petterson, C., Laurell, G. F. E., & Nestor, M. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00825 · Cited by 27 · see citing works
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Glutamine restores mitochondrial respiration in bleomycin-injured epithelial cells
Shaghaghi, H., Para, R., Tran, C., Roman, J., Ojeda-Lassalle, Y., Sun, J., Romero, F., & Summer, R. S. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.10.006 · Cited by 24 · see citing works
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“Glutamine is used as a material for glutathione synthesis (52).”
MethodWang, X., Xiao-xia, Y., Peng-Fei, S., Zong-Xue, Z., & Xiu-li, G. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175323 · Cited by 23 · see citing works
Effects of metabolic cancer therapy on tumor microenvironment
Hyroššová, P., Milošević, M., Škoda, J., Vachtenheim, J., Jr., Rohlena, J., & Rohlenová, K. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1046630 · Cited by 22 · see citing works
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Glutamine Metabolism and Prostate Cancer
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“Inhibition of GLS with BPTES or genetic silencing of GLS or GLS2 increased the radiation sensitivity of lung and prostate tumor cell lines [6,155,156].”
BackgroundHan, L., Zhang, C., Wang, D., Zhang, J., Tang, Q., Li, M. J., Sack, M. N., Wang, L., & Zhu, L. (2023) · Oncogene · doi:10.1038/s41388-023-02621-w · Cited by 20 · see citing works
“High glucose oxidation generates ROS, while glutamine metabolism supplies GSH formation and contributes to an antioxidant system [52].”
BackgroundGlutamate-mediated effects of caffeine and interferon-γ on mercury-induced toxicity
Engin, A. B., Engin, D., Golokhvast, K. S., Spandidos, D. A., & Tsatsakis, A. M. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.2937 · Cited by 20 · see citing works
“Culture in glutamine-free medium reduces cell proliferation and viability and abolishes glutathione excretion (34).”
Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio
van Gisbergen, M. W., Zwilling, E., & Dubois, L. J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.653621 · Cited by 20 · see citing works
Terahertz metamaterial on-chip sensing platform for live cancer cell microenvironment analysis
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Increased glutathione utilization augments tumor cell proliferation in Waldenstrom Macroglobulinemia
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“In addition to glucose metabolism, inhibition of glutamine metabolism enhances radiosensitivity in cancer cells [32], suggesting that amino acid metabolism is also crucial for cancer survival after irradiation.”
BackgroundRabben, H.-L., Kodama, Y., Nakamura, M., Bones, A. M., Wang, T. C., Chen, D., Zhao, C., & Øverby, A. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.613458 · Cited by 18 · see citing works
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“Our data on the striking difference in the glutathione content in the normal and cancer epithelium (Table 2) agree with independent quantifications, which have shown an order of magnitude higher glutathione content in A549 cells, compared to the lung fibroblast cell lines [50,51].”
ResultGlutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort
Zalachoras, I., Ramos‐Fernández, E., Hollis, F., Trovò, L., Rodrigues, J., Strasser, A., Zanoletti, O., Steiner, P., Preitner, N., Xin, L., et al. (2022) · eLife · doi:10.7554/elife.77791 · Cited by 17 · see citing works
Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers
Moss, D., McCann, C. K., & Kerr, E. M. (2022) · Science Signaling · doi:10.1126/scisignal.abj3490 · Cited by 15 · see citing works
Li, D., Cao, D., Zhang, Y., Yu, X., Wu, Y., Jia, Z., Jiang, J., & Cao, X. (2025) · Scientific Reports · doi:10.1038/s41598-024-84916-w · Cited by 15 · see citing works
Rodríguez‐Tomàs, E., Arguís, M., Arenas, M., Fernández‐Arroyo, S., Murcia, M., Sabater, S., Torres, L., Baiges‐Gayà, G., Hernández‐Aguilera, A., Camps, J., et al. (2019) · Journal of Proteomics · doi:10.1016/j.jprot.2019.103605 · Cited by 15 · see citing works
Claiborne, M. D., & Leone, R. D. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1011191 · Cited by 15 · see citing works
“Tumor cells generate extensive free radicals, and a significant portion of extracellular glutamine has been shown to be utilized in glutathione synthesis for maintenance of redox homeostasis in lung cancer models (52).”
BackgroundGlutamine protects intestinal calcium absorption against oxidative stress and apoptosis
Moine, L., de Barboza, G. D., Pérez, A., Benedetto, M. M., & de Talamoni, N. T. (2017) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2017.07.006 · Cited by 15 · see citing works
Thiol-Redox Regulation in Lung Development and Vascular Remodeling
Ofman, G., & Tipple, T. E. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7712 · Cited by 15 · see citing works
“Finally, other sources and potential therapeutic targets for GSH synthesis are the amino acid glutamine, by conversion to glutamate (142) and serine, which affects the biosynthesis of selenium (Se) and, consequently, selenoprotein activity and expression (173).”
BackgroundChen, Y., & Betenbaugh, M. J. (2023) · Metabolic Engineering · doi:10.1016/j.ymben.2023.02.010 · Cited by 13 · see citing works
Critical role of antioxidant programs in enzalutamide-resistant prostate cancer
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“Since amino acid metabolism, especially glutamine metabolism, can regulate antioxidant levels [26], we then examined the regulation of genes involved in both glutamine and antioxidant metabolism.”
BackgroundBoysen, G., Arora, R., Degner, A., Vevang, K. R., Chao, C., Rodriguez, F. F., Walmsley, S. J., Erber, L. N., Tretyakova, N. Y., & Peterson, L. A. (2020) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.0c00376 · Cited by 13 · see citing works
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“Glutaminolysis inhibition suppresses growth or survival and enhances radiosensitivity in some cancer cell lines [11].”
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“Related research shows that glutathione can be involved in DNA repair to protect against side effects caused by tumor drugs and other radiopharmaceuticals and radiotherapy [6,7].”
BackgroundYe, G., Gao, H., Wu, Z., Chen, J., Zhang, J., & Huang, Q. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.145763 · Cited by 12 · see citing works
Gut Microbiome Was Highly Related to the Regulation of Metabolism in Lung Adenocarcinoma Patients
Wang, S., Chen, H., Yang, H., Zhou, K., Bai, F., Wu, X., & Xu, H. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.790467 · Cited by 12 · see citing works
Zeng, L., Zhang, P., Li, J., Yu, Q. S., Zheng, Y., & Li, D. (2022) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2022.114221 · Cited by 11 · see citing works
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Metabolic-Modulating Effects of Radiation: Undetectable Yet Deadly—A Review on Radiotherapy
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Resistance of HEK-293 and COS-7 cell lines to oxidative stress as a model of metabolic response
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Yang, T., Tian, Y., Yang, Y., Tang, M., Shi, M., Chen, Y. X., Yang, Z., & Chen, L. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114686 · Cited by 10 · see citing works
Tomar, M. S., Kulkarni, C., Washimkar, K. R., Verma, S., Bhadkaria, A., Araniti, F., Mugale, M. N., Chattopadhyay, N., & Shrivastava, A. (2025) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5c00734 · Cited by 9 · see citing works
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Diagnosis of lung tumor types based on metabolomic profiles in lymph node aspirates
Sappington, D. R., Helms, S. A., Siegel, E. R., Penney, R. B., Jeffus, S. K., Bartter, T., Bartter, T. C., & Boysen, G. (2017) · Cancer Treatment and Research Communications · doi:10.1016/j.ctarc.2017.08.002 · Cited by 9 · see citing works
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“Studies have found that both metabolic pathways, glycolysis and oxidative phosphorylation, can regulate tumor radiotherapy sensitivity [40].”
BackgroundCB-839 induces reversible dormancy in lung tumor-cells
Jamshidi‐Parsian, A., Jenkins, S. V., Tran, A., Bragg, A., Davis, R., Griffin, C., Siegel, E. R., Dings, R. P. M., Griffin, R. J., & Boysen, G. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176912 · Cited by 8 · see citing works
Self-citationMetabolic signatures associated with oncolytic myxoma viral infections
Mahar, R., Ragavan, M., Chang, M. C., Hardiman, S., Moussatché, N., Behar, A., Renne, R., & Merritt, M. E. (2022) · Scientific Reports · doi:10.1038/s41598-022-15562-3 · Cited by 8 · see citing works
NF-YA overexpression protects from glutamine deprivation
Dolfini, D., Minuzzo, M., Sertic, S., & Mantovani, R. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.118571 · Cited by 7 · see citing works
Mattia, M. D., Sallese, M., & Lopetuso, L. R. (2025) · Acta Physiologica · doi:10.1111/apha.14284 · Cited by 7 · see citing works
“138 Glutamine's alleviation of ER stress could be linked to its antioxidant capabilities since Glutamine is essential for the synthesis of glutathione, 139 which is critical in protecting cells from OS that is strictly linked to ER stress.”
Soumoy, L., Genbauffe, A., Sant’Angelo, D., Everaert, M., Mukeba-Harchies, L., Sarry, J., Declèves, A.-É., & Journé, F. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178241 · Cited by 8 · see citing works
“It can be converted into metabolites of the TCA cycle [15] and is also essential for the synthesis of glutathione [16], proteins, and nucleotides [17].”
Dhawan, A., Pifer, P. M., Sandulache, V. C., & Skinner, H. D. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1016217 · Cited by 7 · see citing works
Zhang, Y., Xie, L., Fujinaga, M., Kurihara, Y., Ogawa, M., Kumata, K., Mori, W., Kokufuta, T., Nengaki, N., Wakizaka, H., et al. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.07.023 · Cited by 6 · see citing works
“The development of small-molecule inhibitors, such as bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) 16 , CB-839 17 , and Compound 968 18 has paved new avenues for metabolism-targeted therapies that modulate GLS1 activity to regulate glutaminolysis.”
Influential
- Authors
- Sappington, D. R., Siegel, E. R., Hiatt, G., Desai, A., Penney, R. B., Jamshidi-Parsian, A., Griffin, R. J., & Boysen, G.
- Affiliations
- University of Arkansas for Medical Sciences (US)
- Corresponding author
- Boysen, Gunnar
- Venue
- Biochimica et Biophysica Acta (BBA) - General Subjects
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 1860
- Issue
- 4
- Pages
- 836-843
- ISSN
- 0304-4165 (ISSN-L)
- PMC
- PMC4768472
- OpenAlex
- W2300605759
- Cited by
- 143
- References
- 43
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 17 · 2023: 14 · 2022: 23 · 2021: 16 · 2020: 22 · 2019: 11 · 2018: 7 · 2017: 10 · 2016: 1
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochimica et Biophysica Acta (BBA) - General Subjects (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) (UL1TR000039, KL2TR000063)
- Arkansas Bioscience Institute
- Envoys
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- glutamine, glutathione synthesis, glutamine addiction, glutaminase inhibition, BPTES, lung cancer, A549 cells, H460 cells, radiosensitivity, glutamate, tumor cell proliferation
- MeSH terms
- Glutamine, Glutathione, Humans, Lung Neoplasms, Radiation Tolerance, Sulfides, Thiadiazoles, X-Rays, Cell Line, Tumor
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