Glutamine anaplerosis is required for amino acid biosynthesis in human meningiomas

Abstract

Background We postulate that meningiomas undergo distinct metabolic reprogramming in tumorigenesis and unravelling 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 33 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 five 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 being statistically significant (p ≤ 0.02). 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) would be very effective in downregulating glutamine metabolic pathways in grade-I meningiomas leading to decreased cellular proliferation.

A comparison of different machine-learning techniques for the selection of a panel of metabolites allowing early detection of brain tumors

“…Moreover, Ijare et al . 64 , in their study, indicated that alanine, glutamine, and glutamate were significantly elevated in MT grade II. They also demonstrated that blocking glutamine metabolism with the GLS1 inhibitor led to a decrease in meningioma cell proliferation.…”

“… 16 , in their study of glioma and MT tissues, reported that patients with MTs had higher levels of aspartic acid, lysine, and arginine. Most metabolomics work on MTs has been done using nuclear magnetic resonance spectroscopy 15 , 62 – 64 . Baranovicova et al .…”

The Interaction between Collagen 1 and High Mannose Type CD133 Up‐Regulates Glutamine Transporter SLC1A5 to Promote the Tumorigenesis of Glioblastoma Stem Cells

“…Glutamine Uptake Assay: The glutamine uptake assay in GSCs was performed as previously described. [53] Briefly, cells were grown in Glnfree DMEM for at least 4 h. Then, 2 mM (U-13 C5)-Gln (Cambridge Isotope Labs) were then added to the medium. Cells were harvested in 80% methanol, and lysates were stored at −80 °C until further analysis by gas chromatography-mass spectrometry (GC-MS) for mass isotopomer distribution of various metabolites.…”

Imaging 2-hydroxyglutarate and other brain oncometabolites pertinent to critical genomic alterations in brain tumors

“…The increased alanine in atypical meningiomas, WHO Grade 2, may be driven by increased glutamate and glutamine precursors, as well as metabolic reprogramming to upregulate alanine as an alternative energy source to support tumor growth. 52 Increased lactate and glycine may also occur in atypical meningiomas, WHO Grade 1. Interestingly, a distinct large peak at 3.8 ppm is also considered to be specific for meningioma, although the cause of the peak and underlying oncometabolite remains uncertain.…”