Omkar B Ijare1, Shashank Hambarde1, Fabio Henrique Brasil da Costa1, Sophie Lopez1, Martyn A Sharpe1, Santosh A Helekar1,2, Gilbert Hangel3,4, Wolfgang Bogner3, Georg Widhalm4, Robert M Bachoo5, David S Baskin1,2, Kumar Pichumani1,2. 1. Kenneth R. Peak Brain and Pituitary Tumor Treatment Center, Department of Neurosurgery, Houston Methodist Neurological Institute, Houston Methodist Hospital and Research Institute, Houston, Texas, USA. 2. Weill Cornell Medical College, New York, New York, USA. 3. High-Field MR Center, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria. 4. Department of Neurosurgery, Medical University of Vienna, Vienna, Austria. 5. Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, Texas, USA.
Abstract
BACKGROUND: We postulate that meningiomas undergo distinct metabolic reprogramming in tumorigenesis and unraveling their metabolic phenotypes provide new therapeutic insights. Glutamine catabolism is key to the growth and proliferation of tumors. Here, we investigated the metabolomics of freshly resected meningiomas and glutamine metabolism in patient-derived meningioma cells. METHODS: 1H NMR spectroscopy of tumor tissues from meningioma patients was used to differentiate the metabolite profiles of grade-I and grade-II meningiomas. Glutamine metabolism was examined using 13C/15N glutamine tracer, in 5 patient-derived meningioma cells. RESULTS: Alanine, lactate, glutamate, glutamine, and glycine were predominantly elevated only in grade-II meningiomas by 74%, 76%, 35%, 75%, and 33%, respectively, with alanine and glutamine levels being statistically significant (P ≤ .02). 13C/15N glutamine tracer experiments revealed that both grade-I and -II meningiomas actively metabolize glutamine to generate various key carbon intermediates including alanine and proline that are necessary for the tumor growth. Also, it is shown that glutaminase (GLS1) inhibitor, CB-839 is highly effective in downregulating glutamine metabolism and decreasing proliferation in meningioma cells. CONCLUSION: Alanine and glutamine/glutamate are mainly elevated in grade-II meningiomas. Grade-I meningiomas possess relatively higher glutamine metabolism providing carbon/nitrogen for the biosynthesis of key nonessential amino acids. GLS1 inhibitor (CB-839) is very effective in downregulating glutamine metabolic pathways in grade-I meningiomas leading to decreased cellular proliferation.
BACKGROUND: We postulate that meningiomas undergo distinct metabolic reprogramming in tumorigenesis and unraveling their metabolic phenotypes provide new therapeutic insights. Glutamine catabolism is key to the growth and proliferation of tumors. Here, we investigated the metabolomics of freshly resected meningiomas and glutamine metabolism in patient-derived meningioma cells. METHODS: 1H NMR spectroscopy of tumor tissues from meningioma patients was used to differentiate the metabolite profiles of grade-I and grade-II meningiomas. Glutamine metabolism was examined using 13C/15N glutamine tracer, in 5 patient-derived meningioma cells. RESULTS: Alanine, lactate, glutamate, glutamine, and glycine were predominantly elevated only in grade-II meningiomas by 74%, 76%, 35%, 75%, and 33%, respectively, with alanine and glutamine levels being statistically significant (P ≤ .02). 13C/15N glutamine tracer experiments revealed that both grade-I and -II meningiomas actively metabolize glutamine to generate various key carbon intermediates including alanine and proline that are necessary for the tumor growth. Also, it is shown that glutaminase (GLS1) inhibitor, CB-839 is highly effective in downregulating glutamine metabolism and decreasing proliferation in meningioma cells. CONCLUSION: Alanine and glutamine/glutamate are mainly elevated in grade-II meningiomas. Grade-I meningiomas possess relatively higher glutamine metabolism providing carbon/nitrogen for the biosynthesis of key nonessential amino acids. GLS1 inhibitor (CB-839) is very effective in downregulating glutamine metabolic pathways in grade-I meningiomas leading to decreased cellular proliferation.
Authors: F A Howe; S J Barton; S A Cudlip; M Stubbs; D E Saunders; M Murphy; P Wilkins; K S Opstad; V L Doyle; M A McLean; B A Bell; J R Griffiths Journal: Magn Reson Med Date: 2003-02 Impact factor: 4.668
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Authors: Roland Goldbrunner; Giuseppe Minniti; Matthias Preusser; Michael D Jenkinson; Kita Sallabanda; Emmanuel Houdart; Andreas von Deimling; Pantelis Stavrinou; Florence Lefranc; Morten Lund-Johansen; Elizabeth Cohen-Jonathan Moyal; Dieta Brandsma; Roger Henriksson; Riccardo Soffietti; Michael Weller Journal: Lancet Oncol Date: 2016-08-30 Impact factor: 41.316