2026-06-01T06:39:34Zhttps://riuma.uma.es/rest/oai/request

oai:riuma.uma.es:10630/362592026-02-03T11:01:34Zcom_10630_2254col_10630_37953

Glutaminase-2 Expression Induces Metabolic Changes and Regulates Pyruvate Dehydrogenase Activity in Glioblastoma Cells De los Santos-Jiménez, Juan Campos-Sandoval, José Ángel Rosales, Tracy Ko, Bookyung Alonso, Francisco J. Márquez-Gómez, Javier DeBerardinis, Ralph J Mates-Sánchez, José Manuel Glioma Glutaminase controls the first step in glutaminolysis, impacting bioenergetics, biosynthesis and oxidative stress. Two isoenzymes exist in humans, GLS and GLS2. GLS is considered prooncogenic and overexpressed in many tumours, while GLS2 may act as prooncogenic or as a tumour suppressor. Glioblastoma cells usually lack GLS2 while they express high GLS. We investigated how GLS2 expression modifies the metabolism of glioblastoma cells, looking for changes that may explain GLS2’s potential tumour suppressive role. We developed LN-229 glioblastoma cells stably expressing GLS2 and performed isotope tracing using U-13C-glutamine and metabolomic quantification to analyze metabolic changes. Treatment with GLS inhibitor CB-839 was also included to concomitantly inhibit endogenous GLS. GLS2 overexpression resulted in extensive metabolic changes, altering the TCA cycle by upregulating part of the cycle but blocking the synthesis of the 6-carbon intermediates from acetyl-CoA. Expression of GLS2 caused downregulation of PDH activity through phosphorylation of S293 of PDHA1. GLS2 also altered nucleotide levels and induced the accumulation of methylated metabolites and S-adenosyl methionine. These changes suggest that GLS2 may be a key regulator linking glutamine and glucose metabolism, also impacting nucleotides and epigenetics. Future research should ascertain the mechanisms involved and the generalizability of these findings in cancer or physiological conditions. 2025-01-14T08:21:47Z 2025-01-14T08:21:47Z 2025-01-07 2025-01-06 journal article De los Santos-Jiménez, J.; Campos-Sandoval, J.A.; Rosales, T.; Ko, B.; Alonso, F.J.; Márquez, J.; DeBerardinis, R.J.; Matés, J.M. Glutaminase-2 Expression Induces Metabolic Changes and Regulates Pyruvate Dehydrogenase Activity in Glioblastoma Cells. Int. J. Mol. Sci. 2025, 26, 427. https://doi.org/10.3390/ijms26010427 https://hdl.handle.net/10630/36259 10.3390/ijms26010427 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional MDPI