Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Glycolysis in Cancer Cells
2.1. The Warburg Effect and Glucose Avidity in Glioblastoma
2.2. Glycolytic Enzymes in Glioma
2.2.1. Hexokinase 2
2.2.2. Glucose-6-Phosphate Isomerase (G6PI)
2.2.3. Phosphofructokinase
2.2.4. Aldolase
2.2.5. Glyceraldehyde 3 Phosphate Dehydrogenase
2.2.6. Phosphoglycerate Kinase (PGK)
2.2.7. Phosphoglycerate Mutase (PGM)
2.2.8. Enolase
2.2.9. Pyruvate Kinase
2.2.10. Lactate Dehydrogenase
2.3. Therapeutic Implications of Glycolysis and Lipid Metabolism in the Apoptosis Regulation in Glioma
2.4. Regulation of the Autophagy by Glycolysis and Lipid Metabolism
2.5. Glycolysis as a Target of Therapeutic Drugs in Gliomas
3. Glutaminase Pathway
3.1. Glutaminase Pathway in Glioblastoma
3.1.1. Glutamine Synthetase
3.1.2. Glutaminase
3.1.3. Glutamate Dehydrogenase
3.2. Regulation of the Autophagy by Glutamine
3.3. Glutaminolisis as a Target of Therapeutic Drugs in Gliomas
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Target | Treatment | Clinical and Preclinical Trials |
---|---|---|
Glycolysis | ||
Glycolysis pathway | Methylene blue | Increased OCR and decreased ECAR and lactate production in glioblastoma cell lines [223]. |
Enolase | HEX and POMHEX | Decrease in TCA cycle metabolites using a glioma cell expressing ENO2 but no ENO1 [136]. |
Pyruvate Dehydrogenase Kinases (PDHK) | Dichloroacetate (DCA) | Increased the oxidative phosphorylation in vitro. Also, induces cell death in glioma cells, through the generation of ROS with a decrease in p53, HIF-1, p21, proliferating cell nuclear antigen (PCNA), hexokinase 2, VEGF, and α-ketoglutarate [224,225]. |
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3). | 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) | In complement to bevacizumab, decreased cell proliferation and increased apoptosis in vitro, whereas delayed tumor growth and improved survival using in vivo [226] |
Syk inhibitor | R406 | Shifts the glioma cells from a glycolytic profile toward OXPHOS metabolism, and increases apoptosis [227]. |
Monocarboxylate transporter 4 (MCT4) | Acriflavine | Decrease cell proliferation and tumoral growth [228,229]. |
Histone deacetylase (HDAC) | Vorinostat | Decrease intracellular lactate, cell viability, and tumor progression [230]. |
Glutaminolysis | ||
Glutaminase (GLS) | Compound 968 | Inhibit the glioma cell growth with the Notch pathway blocked [231,232,233] |
bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES). | Slows GBM growth cell with IDH1mut [234]. | |
CB-839 | Reduced proliferation, angiogenesis, and modestly increased apoptosis in glioma stem-like cells with IDH1mut [235,236,237]. | |
Glutamine Synthetase (GS) | Actinomycin D, 5-azacytidine. | Decreased proliferation in glioma cells [231]. |
Carnosine | Suppressed growth and migration in glioma cells [238]. | |
Glutamine | Acivicin, 6-diazo-5-oxo-L-norleucine (DON). | Inhibit the growth of glioma cells [231]. |
6-diazo-5-oxo-L-norleucine (DON) plus L-asparaginase. | Induces apoptosis and autophagy in glioma cells by the depletion of asparagine via inhibition of asparagine synthetase [232]. | |
JHU-083 | Inhibits cell growth and mTOR signaling [239]. | |
Glutamate | GLT1 cDNA overexpression. | Inhibits growth proliferation in glioma cells [240]. |
xCT | Sulfasalazine | Induce apoptosis in GBM cells [241]. |
GLAST | shGLAST | Increases survival in glioma-bearing mice [242]. |
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Trejo-Solis, C.; Silva-Adaya, D.; Serrano-García, N.; Magaña-Maldonado, R.; Jimenez-Farfan, D.; Ferreira-Guerrero, E.; Cruz-Salgado, A.; Castillo-Rodriguez, R.A. Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma. Int. J. Mol. Sci. 2023, 24, 17633. https://doi.org/10.3390/ijms242417633
Trejo-Solis C, Silva-Adaya D, Serrano-García N, Magaña-Maldonado R, Jimenez-Farfan D, Ferreira-Guerrero E, Cruz-Salgado A, Castillo-Rodriguez RA. Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma. International Journal of Molecular Sciences. 2023; 24(24):17633. https://doi.org/10.3390/ijms242417633
Chicago/Turabian StyleTrejo-Solis, Cristina, Daniela Silva-Adaya, Norma Serrano-García, Roxana Magaña-Maldonado, Dolores Jimenez-Farfan, Elizabeth Ferreira-Guerrero, Arturo Cruz-Salgado, and Rosa Angelica Castillo-Rodriguez. 2023. "Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma" International Journal of Molecular Sciences 24, no. 24: 17633. https://doi.org/10.3390/ijms242417633