Glutamine anaplerosis is required for amino acid biosynthesis in human meningiomas
| Autor: | Wolfgang Bogner, Omkar B. Ijare, Martyn A. Sharpe, David S. Baskin, Santosh A. Helekar, Sophie Lopez, Fabio Henrique Brasil da Costa, Gilbert Hangel, Robert Bachoo, Shashank Hambarde, Kumar Pichumani, Georg Widhalm |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Glutamine Meningioma chemistry.chemical_compound Biosynthesis Cell Line Tumor Meningeal Neoplasms otorhinolaryngologic diseases medicine Humans neoplasms Amino acid synthesis chemistry.chemical_classification Alanine Glutaminase medicine.disease nervous system diseases Amino acid Oncology chemistry Biochemistry Basic and Translational Investigations Glycine Neurology (clinical) |
| Zdroj: | Neuro Oncol |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/noab219 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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