Extracellular glutamate and IDH1 R132H inhibitor promote glioma growth by boosting redox potential.

Autor: Tiburcio PDB; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, USA.; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA., Gillespie DL; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, USA., Jensen RL; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, USA.; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA., Huang LE; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, USA. eric.huang@hsc.utah.edu.; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA. eric.huang@hsc.utah.edu.
Jazyk: angličtina
Zdroj: Journal of neuro-oncology [J Neurooncol] 2020 Feb; Vol. 146 (3), pp. 427-437. Date of Electronic Publication: 2020 Feb 04.
DOI: 10.1007/s11060-019-03359-w
Abstrakt: Purpose: Somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, mostly substituting Arg132 with histidine, are associated with better patient survival, but glioma recurrence and progression are nearly inevitable, resulting in disproportionate morbidity and mortality. Our previous studies demonstrated that in contrast to hemizygous IDH1 R132H (loss of wild-type allele), heterozygous IDH1 R132H is intrinsically glioma suppressive but its suppression of three-dimensional (3D) growth is negated by extracellular glutamate and reducing equivalent. This study sought to understand the importance of 3D culture in IDH1 R132H biology and the underlying mechanism of the glutamate effect.
Methods: RNA sequencing data of IDH1 R132H -heterozygous and IDH1 R132H -hemizygous glioma cells cultured under two-dimensional (2D) and 3D conditions were subjected to unsupervised hierarchal clustering and gene set enrichment analysis. IDH1 R132H -heterozygous and IDH1 R132H -hemizygous tumor growth were compared in subcutaneous and intracranial transplantations. Short-hairpin RNA against glutamate dehydrogenase 2 gene (GLUD2) expression was employed to determine the effects of glutamate and the mutant IDH1 inhibitor AGI-5198 on redox potential in IDH1 R132H -heterozygous cells.
Results: In contrast to IDH1 R132H -heterozygous cells, 3D-cultured but not 2D-cultured IDH1 R132H -hemizygous cells were clustered with more malignant gliomas, possessed the glioblastoma mesenchymal signature, and exhibited aggressive tumor growth. Although both extracellular glutamate and AGI-5198 stimulated redox potential for 3D growth of IDH1 R132H -heterozygous cells, GLUD2 expression was required for glutamate, but not AGI-5198, stimulation.
Conclusion: 3D culture is more relevant to IDH1 R132H glioma biology. The importance of redox homeostasis in IDH1 R132H glioma suggests that metabolic pathway(s) can be explored for therapeutic targeting, whereas IDH1 R132H inhibitors may have counterproductive consequences in patient treatment.
Databáze: MEDLINE
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