Glutaminase isoforms expression switches microRNA levels and oxidative status in glioblastoma cells
Open Access
- 20 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Biomedical Science
- Vol. 28 (1), 1-16
- https://doi.org/10.1186/s12929-021-00712-y
Abstract
Glutaminase isoenzymes GLS and GLS2 play apparently opposing roles in cancer: GLS acts as an oncoprotein, while GLS2 (GAB isoform) has context specific tumour suppressive activity. Some microRNAs (miRNAs) have been implicated in progression of tumours, including gliomas. The aim was to investigate the effect of GLS and GAB expression on both miRNAs and oxidative status in glioblastoma cells. Microarray profiling of miRNA was performed in GLS-silenced LN229 and GAB-transfected T98G human glioblastoma cells and their wild-type counterparts. Results were validated by real-time quantitative RT-PCR. Oxidative status and antioxidant enzymes were determined by spectrophotometric or fluorescence assays in GLS-silenced LN229 and T98G, and GAB-transfected LN229 and T98G. MiRNA-146a-5p, miRNA-140-3p, miRNA-21-5p, miRNA-1260a, and miRNA-92a-3p were downregulated, and miRNA-1246 was upregulated when GLS was knocked down. MiRNA-140-3p, miRNA-1246, miRNA-1260a, miRNA-21-5p, and miRNA-146a-5p were upregulated when GAB was overexpressed. Oxidative status (lipid peroxidation, protein carbonylation, total antioxidant capacity, and glutathione levels), as well as antioxidant enzymes (catalase, superoxide dismutase, and glutathione reductase) of silenced GLS glioblastoma cells and overexpressed GAB glioblastoma cells significantly changed versus their respective control glioblastoma cells. MiRNA-1246, miRNA-1260a, miRNA-146a-5p, and miRNA-21-5p have been characterized as strong biomarkers of glioblastoma proliferation linked to both GLS silencing and GAB overexpression. Total glutathione is a reliable biomarker of glioblastoma oxidative status steadily associated to both GLS silencing and GAB overexpression. Glutaminase isoenzymes are related to the expression of some miRNAs and may contribute to either tumour progression or suppression through certain miRNA-mediated pathways, proving to be a key tool to switch cancer proliferation and redox status leading to a less malignant phenotype. Accordingly, GLS and GAB expression are especially involved in glutathione-dependent antioxidant defence.Keywords
Funding Information
- Ministerio de Ciencia y Tecnología (RTI2018-096866-B-I00)
- Ministerio de Ciencia y Tecnología (RTI2018-096866-B-I00)
- Howard Hughes Medical Institute
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
- Cancer Prevention and Research Institute of Texas
- Moody's Foundation
- CAPES (CAPES/DGU 250/11)
- Ministerio de Ciencia, Innovación y Universidades (FPU17/04084)
This publication has 79 references indexed in Scilit:
- miR-92a is a critical regulator of the apoptosis pathway in glioblastoma with inverse expression of BCL2L11Oncology Reports, 2012
- The Metabolic Profile of Tumors Depends on Both the Responsible Genetic Lesion and Tissue TypeCell Metabolism, 2012
- Pyruvate carboxylase is required for glutamine-independent growth of tumor cellsProceedings of the National Academy of Sciences of the United States of America, 2011
- Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant functionProceedings of the National Academy of Sciences of the United States of America, 2010
- Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen speciesProceedings of the National Academy of Sciences of the United States of America, 2010
- New insights into brain glutaminases: Beyond their role on glutamatergic transmissionNeurochemistry International, 2009
- c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolismNature, 2009
- MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98GCancer Letters, 2008
- MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma CellsCancer Research, 2008
- Impairment of Both Apoptotic and Cytoprotective Signalings in Glioma Cells Resistant to the Combined Use of Cisplatin and Tumor Necrosis Factor αClinical Cancer Research, 2004