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- W2954102945 abstract "Measurement and Methods: In this study, we sought to expand our knowledge of glutamine metabolism beyond glutaminolysis. Using mass spectroscopy-based stable isotope-resolved metabolomics (SIRM) with 13C515N2-labeled-glutamine, we precisely identified the metabolites produced from glutamine both in vitro and in vivo. Tumors were harvested 2 hours post first glutamine injection. Metabolites were then extracted from tumors, and analyzed using Agilent 6520 Q-TOF mass spectrometer and 1H-NMR. Metabolite intensities were later normalized to protein concentration following analysis. Results: Our results showed that total glutamate levels were lower in BPTES-NP treated tumors as compared to vehicle control ones. Interestingly, we found an increase in (m+5) labeled glutamate (mass of the parent ions (m) and 5 more mass units due to 13C415N1-glutamate or 13C5-glutamate labelling) in BPTES-NP treated tumors as compared to the vehicle control tumors. Moreover, we found that (m+5) glutamate is a product of (m+7) glutamine being converted to (m+5) alpha-ketoglutaramate (KGM) via glutamine-pyruvate transaminase and further on into alpha-ketoglutarate (aKG) by omega-amidase, which can finally produce the identified (m+5) glutamate through glutamate dehydrogenase. Further analysis using 1H-NMR detailed a significant increase in overall KGM intermediate intensity in treatment groups compared to the control groups, confirming the upregulation of compensatory pathway (glutamine-KGM- aKG-glutamate) to produce glutamate upon treatment of GLS1 inhibitor. Conclusion: These results explain the reasons behind the limited clinical outcomes for single therapy with a GLS1 inhibitor, and provide potential therapeutic targets: glutamine-pyruvate transaminase, for combination treatments with GLS1 inhibitors to prevent the compensation for glutamate production amid GLS1 inhibition. Citation Format: Ryoichi Asaka, Tu Nguyen, Brian J. Krisch, Karim Nabi, Addison Quinones, Jessica Tan, Marjorie J. Antonio, Ting Li, Felipe Camelo, Kiet Nguyen, Sunag Udupa, Edward Gabrielson, Anne Le. Identification of compensatory pathway for glutamate production [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 803." @default.
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- W2954102945 date "2019-07-01" @default.
- W2954102945 modified "2023-09-26" @default.
- W2954102945 title "Abstract 803: Identification of compensatory pathway for glutamate production" @default.
- W2954102945 doi "https://doi.org/10.1158/1538-7445.sabcs18-803" @default.
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