Glutamine anaplerosis is required for amino acid biosynthesis in human meningiomas

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 24; no. 4; pp. 556 - 568
• Main Authors: Ijare, Omkar B, Hambarde, Shashank, Brasil da Costa, Fabio Henrique, Lopez, Sophie, Sharpe, Martyn A, Helekar, Santosh A, Hangel, Gilbert, Bogner, Wolfgang, Widhalm, Georg, Bachoo, Robert M, Baskin, David S, Pichumani, Kumar
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.04.2022
• Subjects: Amino Acids; Basic and Translational Investigations; Child; Glutamic Acid - metabolism; Glutamine - metabolism; Humans; Magnetic Resonance Spectroscopy - methods; Meningeal Neoplasms - metabolism; Meningioma - metabolism; meningioma; alanine; metabolic flux analysis; glutamine; metabolomics
• ISSN: 1522-8517; 1523-5866; 1523-5866
• DOI: 10.1093/neuonc/noab219

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.