PUBLICATION
Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression
- Authors
- Franceschi, S., Corsinovi, D., Lessi, F., Tantillo, E., Aretini, P., Menicagli, M., Scopelliti, C., Civita, P., Pasqualetti, F., Naccarato, A.G., Ori, M., Mazzanti, C.M.
- ID
- ZDB-PUB-181014-1
- Date
- 2018
- Source
- EBioMedicine 37: 56-67 (Journal)
- Registered Authors
- Keywords
- GLUD2, Glioblastoma, Glutamate, Mitochondrial metabolism, Tumor progression, Zebrafish
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- Glioblastoma/genetics
- Glioblastoma/metabolism*
- Glioblastoma/pathology
- Glutamate Dehydrogenase/genetics
- Glutamate Dehydrogenase/metabolism*
- Humans
- Mitochondrial Proteins/genetics
- Mitochondrial Proteins/metabolism*
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism*
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 30314897 Full text @ EBioMedicine
Citation
Franceschi, S., Corsinovi, D., Lessi, F., Tantillo, E., Aretini, P., Menicagli, M., Scopelliti, C., Civita, P., Pasqualetti, F., Naccarato, A.G., Ori, M., Mazzanti, C.M. (2018) Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression. EBioMedicine. 37:56-67.
Abstract
Background Glioblastoma (GBM) is the most frequent and malignant primary brain tumor in adults and despite the progress in surgical procedures and therapy options, the overall survival remains very poor. Glutamate and α-KG are fundamental elements necessary to support the growth and proliferation of GBM cells. Glutamate oxidative deamination, catalyzed by GLUD2, is the predominant pathway for the production of α-KG.
Methods GLUD2 emerged from the RNA-seq analysis of 13 GBM patients, performed in our laboratory and a microarray analysis of 77 high-grade gliomas available on the Geo database. Thereafter, we investigated GLUD2 relevance in cancer cell behavior by GLUD2 overexpression and silencing in two different human GBM cell lines. Finally, we overexpressed GLUD2 in-vivo by using zebrafish embryos and monitored the developing central nervous system.
Findings GLUD2 expression was found associated to the histopathological classification, prognosis and survival of GBM patients. Moreover, through in-vitro functional studies, we showed that differences in GLUD2 expression level affected cell proliferation, migration, invasion, colony formation abilities, cell cycle phases, mitochondrial function and ROS production. In support of these findings, we also demonstrated, with in-vivo studies, that GLUD2 overexpression affects glial cell proliferation without affecting neuronal development in zebrafish embryos.
Interpretation We concluded that GLUD2 overexpression inhibited GBM cell growth suggesting a novel potential drug target for control of GBM progression. The possibility to enhance GLUD2 activity in GBM could result in a blocked/reduced proliferation of GBM cells without affecting the survival of the surrounding neurons.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping