RT Journal Article
T1 Glutaminase-2 Expression Induces Metabolic Changes and Regulates Pyruvate Dehydrogenase Activity in Glioblastoma Cells
A1 De los Santos-Jiménez, Juan
A1 Campos-Sandoval, José Ángel
A1 Rosales, Tracy
A1 Ko, Bookyung
A1 Alonso, Francisco J.
A1 Márquez-Gómez, Javier
A1 DeBerardinis, Ralph J
A1 Mates-Sánchez, José Manuel
K1 Glioma
AB Glutaminase controls the first step in glutaminolysis, impacting bioenergetics,biosynthesis and oxidative stress. Two isoenzymes exist in humans, GLS and GLS2. GLSis considered prooncogenic and overexpressed in many tumours, while GLS2 may actas prooncogenic or as a tumour suppressor. Glioblastoma cells usually lack GLS2 whilethey express high GLS. We investigated how GLS2 expression modifies the metabolism ofglioblastoma cells, looking for changes that may explain GLS2’s potential tumour suppressiverole. We developed LN-229 glioblastoma cells stably expressing GLS2 and performedisotope tracing using U-13C-glutamine and metabolomic quantification to analyze metabolicchanges. Treatment with GLS inhibitor CB-839 was also included to concomitantly inhibitendogenous GLS. GLS2 overexpression resulted in extensive metabolic changes, alteringthe TCA cycle by upregulating part of the cycle but blocking the synthesis of the6-carbon intermediates from acetyl-CoA. Expression of GLS2 caused downregulation ofPDH activity through phosphorylation of S293 of PDHA1. GLS2 also altered nucleotidelevels and induced the accumulation of methylated metabolites and S-adenosyl methionine.These changes suggest that GLS2 may be a key regulator linking glutamine andglucose metabolism, also impacting nucleotides and epigenetics. Future research shouldascertain the mechanisms involved and the generalizability of these findings in cancer orphysiological conditions.
PB MDPI
YR 2025
FD 2025-01-06
LK https://hdl.handle.net/10630/36259
UL https://hdl.handle.net/10630/36259
LA eng
NO 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
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 20 ene 2026