Zoltán Hujber1, Gergő Horváth2, Gábor Petővári1, Ildikó Krencz1, Titanilla Dankó1, Katalin Mészáros3, Hajnalka Rajnai1, Norbert Szoboszlai4, William P. J. Leenders5, András Jeney1, László Tretter2, and Anna Sebestyén1
1 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, Hungary
2 Department of Medical Biochemistry, MTA-SE Laboratory for Neurobiochemistry, Semmelweis University, Budapest, Hungary
3 Hungarian Academy of Sciences - Momentum Hereditary Endocrine Tumours Research Group, Semmelweis University - National Bionics Program, Budapest, Hungary
4 Laboratory of Environmental Chemistry and Bioanalytics, Department of Analytical Chemistry, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary
5 Department of Biochemistry, Radboud University Medical Center, Nijmegen, The Netherlands
Introduction: Glioblastoma is aggressive malignant brain tumor with poor prognosis in adults. Describing alterations in metabolic rewiring may help to identify new druggable targets in cancer research. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in central nervous system, but its effect on cellular oxidation and proliferation has not been investigated previously in human glioma cells.
Aim: Substrate oxidation of human glioma cell lines was studied focusing GABA, glutamine, glutamate utilizations and their role in proliferation.
Methods: U251 MG, U251 MG IDH1 R132H overexpressing cells, U373 MG, U87 MG glioma cell lines were used in vitro. Cellular respiration, glycolysis and substrates oxidation were analyzed by Seahorse technique. Substrate consumption related protein expressions, proliferation rates were assessed. In addition, protein expression of human glioma biopsies was studied by immunohistochemistry.
Results: U251 glioma cells were characterised by high levels of glutamine, glutamate and GABA oxidation. Succinic semialdehyde dehydrogenase (SSADH) expression was correlated to GABA oxidation capacity and increased proliferation rates. Mutant IDH1 protein expression and 2-HG treatment reduced glutamine, GABA oxidation and decreased the pro-proliferative effect of GABA in SSADH expressing cells in vitro. The overexpression of SSADH protein was detected in almost all studied human cases, however, there was no significant association between SSADH expression and clinicopathological parameters (e.g. IDH mutation).
Conclusion: Based on our results, glioma cells with the described SSADH expression are able to use GABA as energy substrate. This potential GABA oxidation and the detected high SSADH expression may contribute to the proliferation and worse prognosis of human gliomas. Therefore, both could be additional therapeutic targets in gliomas.
Doctoral School: Pathology
Supervisor: Anna Sebestyén
E-mail address: firstname.lastname@example.org
oral / poster presentation
Supported by ÚNKP-18-3 and Richter Centenárium Fund, Bolyai Found of Hungarian Academy Sciences, by Semmelweis University Innovation Found STIA-KF-17 and National Bionics Program of Hungary.