[en] BACKGROUND: Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzyme activity is crucial for the generation of reducing potential in normal cells, yet the impact of the mutation on the cellular antioxidant system in glioma is not understood. The aim of this study was to determine how glutathione (GSH), the main antioxidant in the brain, is maintained in IDH1-mutant gliomas, despite an altered NADPH/NADP balance. METHODS: Proteomics, metabolomics, metabolic tracer studies, genetic silencing, and drug targeting approaches in vitro and in vivo were applied. Analyses were done in clinical specimen of different glioma subtypes, in glioma patient-derived cell lines carrying the endogenous IDH1 mutation and corresponding orthotopic xenografts in mice. RESULTS: We find that cystathionine-γ-lyase (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis, is specifically upregulated in IDH1-mutant astrocytomas. CSE inhibition sensitized these cells to cysteine depletion, an effect not observed in IDH1 wild-type gliomas. This correlated with an increase in reactive oxygen species and reduced GSH synthesis. Propargylglycine (PAG), a brain-penetrant drug specifically targeting CSE, led to delayed tumor growth in mice. CONCLUSIONS: We show that IDH1-mutant astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis via CSE to maintain the antioxidant defense, which highlights a novel metabolic vulnerability that may be therapeutically exploited.
Disciplines :
Oncology
Author, co-author :
Cano-Galiano, Andrés; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
Oudin, Anais; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
Fack, Fred; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
Allega, Maria-Francesca; Cancer Research UK Beatson Institute, Glasgow, UK. ; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Sumpton, David; Cancer Research UK Beatson Institute, Glasgow, UK.
Martinez-Garcia, Elena; Quantitative Biology Unit, Luxembourg Institute of Health, Luxembourg, Luxembourg.
DITTMAR, Gunnar ; Quantitative Biology Unit, Luxembourg Institute of Health, Luxembourg, Luxembourg.
Hau, Ann-Christin; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
De Falco, Alfonso; National Center of Genetics, Laboratoire national de santé, Dudelange, Luxembourg.
Herold-Mende, Christel; Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
Bjerkvig, Rolf; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg. ; Department of Biomedicine, University of Bergen, Bergen, Norway.
MEISER, Johannes ; Cancer Metabolism Group, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
Tardito, Saverio; Cancer Research UK Beatson Institute, Glasgow, UK. ; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
NICLOU, Simone P. ; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg. ; Department of Biomedicine, University of Bergen, Bergen, Norway.
Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807-1812.
Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803-820.
Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739-744.
Jiang L, Shestov AA, Swain P, et al. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature. 2016;532(7598):255-258.
Bleeker FE, Atai NA, Lamba S, et al. The prognostic IDH1(R132) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol. 2010;119(4):487-494.
Shi J, Sun B, Shi W, et al. Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumour Biol. 2015;36(2):655-662.
Juratli TA, Lautenschläger T, Geiger KD, et al. Radio-chemotherapy improves survival in IDH-mutant, 1p/19q non-codeleted secondary highgrade astrocytoma patients. J Neurooncol. 2015;124(2):197-205.
Li K, Ouyang L, He M, et al. IDH1 R132H mutation regulates glioma chemosensitivity through Nrf2 pathway. Oncotarget. 2017;8(17):28865-28879.
Reitman ZJ, Jin G, Karoly ED, et al. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci USA. 2011;108(8):3270-3275.
Fack F, Tardito S, Hochart G, et al. Altered metabolic landscape in IDHmutant gliomas affects phospholipid, energy, and oxidative stress pathways. EMBO Mol Med. 2017;9(12):1681-1695.
Trong PD, Jungwirth G, Yu T, et al. Large-Scale drug screening in patientderived idh(mut) glioma stem cells identifies several efficient drugs among FDA-approved antineoplastic agents. Cells. 2020;9(6):1389.
Dao Trong P, Rösch S, Mairbäurl H, et al. Identification of a prognostic hypoxia-associated gene set in IDH-mutant glioma. Int J Mol Sci. 2018;19(10):2903.
Dettling S, Stamova S, Warta R, et al. Identification of CRKII, CFL1, CNTN1, NME2, and TKT as novel and frequent T-Cell targets in human IDH-Mutant Glioma. Clin Cancer Res. 2018;24(12):2951-2962.
Bougnaud S, Golebiewska A, Oudin A, et al. Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma. Oncotarget. 2016;7(22):31955-31971.
Bowman RL, Wang Q, Carro A, Verhaak RG, Squatrito M. GlioVis data portal for visualization and analysis of brain tumor expression datasets. Neuro Oncol. 2017;19(1):139-141.
Tardito S, Oudin A, Ahmed SU, et al. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat Cell Biol. 2015;17(12):1556-1568.
Vande Voorde J, Ackermann T, Pfetzer N, et al. Improving the metabolic fidelity of cancer models with a physiological cell culture medium. Sci Adv. 2019;5(1):eaau7314.
Meiser J, Tumanov S, Maddocks O, et al. Serine one-carbon catabolism with formate overflow. Sci adv. 2016;2(10):e1601273.
Golebiewska A, Hau AC, Oudin A, et al. Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology. Acta Neuropathol. 2020;140(6):919-949.
McBean GJ. The transsulfuration pathway: a source of cysteine for glutathione in astrocytes. Amino Acids. 2012;42(1):199-205.
McBean GJ. Cysteine, glutathione, and thiol redox balance in astrocytes. Antioxidants (Basel). 2017;6(3):62.
Luchman HA, Chesnelong C, Cairncross JG, Weiss S. Spontaneous loss of heterozygosity leading to homozygous R132H in a patient-derived IDH1 mutant cell line. Neuro Oncol. 2013;15(8):979-980.
Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th ed. New York: W H Freeman; 2002. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK21154/
Psychogios N, Hau DD, Peng J, et al. The human serum metabolome. PLoS One. 2011;6(2):e16957.
Engelborghs S, Marescau B, De Deyn PP. Amino acids and biogenic amines in cerebrospinal fluid of patients with Parkinson's disease. Neurochem Res. 2003;28(8):1145-1150.
Sun Q, Collins R, Huang S, et al. Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H(2)S. J Biol Chem. 2009;284(5):3076-3085.
Szabo C, Papapetropoulos A. International union of basic and clinical pharmacology. CII: pharmacological modulation of H2S levels: H2S donors and H2S biosynthesis inhibitors. Pharmacol Rev. 2017;69(4):497-564.
Mosharov E, Cranford MR, Banerjee R. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry. 2000;39(42):13005-13011.
Tang X, Fu X, Liu Y, Yu D, Cai SJ, Yang C. Blockade of glutathione metabolism in IDH1-Mutated Glioma. Mol Cancer Ther. 2020;19(1):221-230.
Han S, Liu Y, Cai SJ, et al. IDH mutation in glioma: molecular mechanisms and potential therapeutic targets. Br J Cancer. 2020;122(11):1580-1589.
Kandil S, Brennan L, McBean GJ. Glutathione depletion causes a JNK and p38MAPK-mediated increase in expression of cystathioninegamma- lyase and upregulation of the transsulfuration pathway in C6 glioma cells. Neurochem Int. 2010;56(4):611-619.
Branzoli F, Pontoizeau C, Tchara L, et al. Cystathionine as a marker for 1p/19q codeleted gliomas by in vivo magnetic resonance spectroscopy. Neuro Oncol. 2019;21(6):765-774.
Zhu J, Berisa M, Schwörer S, Qin W, Cross JR, Thompson CB. Transsulfuration activity can support cell growth upon extracellular cysteine limitation. Cell Metab. 2019;30(5):865-876.e5.
Bélanger M, Allaman I, Magistretti PJ. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 2011;14(6):724-738.
Paul BD, Sbodio JI, Snyder SH. cysteine metabolism in neuronal redox homeostasis. Trends Pharmacol Sci. 2018;39(5):513-524.
Wang XF, Cynader MS. Astrocytes provide cysteine to neurons by releasing glutathione. J Neurochem. 2000;74(4):1434-1442.
Singer E, Judkins J, Salomonis N, et al. Reactive oxygen speciesmediated therapeutic response and resistance in glioblastoma. Cell Death Dis. 2015;6:e1601.
Chen L, Li X, Liu L, Yu B, Xue Y, Liu Y. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function. Oncol Rep. 2015;33(3):1465-1474.
Polewski MD, Reveron-Thornton RF, Cherryholmes GA, Marinov GK, Cassady K, Aboody KS. Increased expression of system xc- in glioblastoma confers an altered metabolic state and temozolomide resistance. Mol Cancer Res. 2016;14(12):1229-1242.
Takeuchi S, Wada K, Nagatani K, Otani N, Osada H, Nawashiro H. Sulfasalazine and temozolomide with radiation therapy for newly diagnosed glioblastoma. Neurol India. 2014;62(1):42-47.
Robe PA, Martin D, Albert A, Deprez M, Chariot A, Bours V. A phase 1-2, prospective, double blind, randomized study of the safety and efficacy of Sulfasalazine for the treatment of progressing malignant gliomas: study protocol of [ISRCTN45828668]. BMC Cancer. 2006;6:29.
Weber CK, Liptay S, Wirth T, Adler G, Schmid RM. Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology. 2000;119(5):1209-1218.
Wahl C, Liptay S, Adler G, Schmid RM. Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Invest. 1998;101(5):1163-1174.
McBrayer SK, Mayers JR, DiNatale GJ, et al. Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell. 2018;175(1):101-116.e25.
Cho ES, Hovanec-Brown J, Tomanek RJ, Stegink LD. Propargylglycine infusion effects on tissue glutathione levels, plasma amino acid concentrations and tissue morphology in parenterally-fed growing rats. J Nutr. 1991;121(6):785-794.
Cramer SL, Saha A, Liu J, et al. Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat Med. 2017;23(1):120-127.
