Hypoxia and succinate antagonize 2-deoxyglucose effects on glioblastoma

• Published in: Biochemical pharmacology 2010-11, Vol.80 (10), p.1517-1527
• Main Authors: Pistollato, Francesca, Abbadi, Sara, Rampazzo, Elena, Viola, Giampietro, Puppa, Alessandro Della, Cavallini, Lucia, Frasson, Chiara, Persano, Luca, Panchision, David M., Basso, Giuseppe
• Format: Article
• Language: English
• Subjects: 2-Deoxyglucose; Adult; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Brain - drug effects; Brain - metabolism; Brain - pathology; Cell Adhesion - drug effects; Cell Culture Techniques; Cell Differentiation - drug effects; Cell Hypoxia - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Child; Deoxyglucose - pharmacology; GBM differentiation; Glioblastoma - metabolism; Glioblastoma - pathology; Glutathione - metabolism; Glycolysis; Humans; Hypoxia; Hypoxia inducible factor-1α; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunohistochemistry; Medical sciences; Membrane Potential, Mitochondrial - drug effects; Neurology; Oxygen - pharmacology; Pharmacology. Drug treatments; Prolyl hydroxylase 2; Reactive Oxygen Species - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Succinate Dehydrogenase - metabolism; Succinic Acid - metabolism; Succinic Acid - pharmacology; Tumors of the nervous system. Phacomatoses
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2010.08.003

Glioblastoma multiforme (GBM) are highly proliferative brain tumors characterized by a hypoxic microenvironment which controls GBM stem cell maintenance. Tumor hypoxia promotes also elevated glycolytic rate; thus, limiting glucose metabolism is a potential approach to inhibit tumor growth. Here we investigate the effects mediated by 2-deoxyglucose (2-DG), a glucose analogue, on primary GBM-derived cells maintained under hypoxia. Our results indicate that hypoxia protects GBM cells from the apoptotic effect elicited by 2-DG, which raises succinate dehydrogenase activity thus promoting succinate level decrease. As a consequence hypoxia inducible factor-1α (HIF-1α) degradation occurs and this induces GBM cells to acquire a neuronal committed phenotype. By adding succinate these effects are reverted, as succinate stabilizes HIF-1α and increases GBM stem cell fraction particularly under hypoxia, thus preserving the tumor stem cell niche. 2-DG inhibits anaerobic glycolysis altering GBM cell phenotype by forcing tumor cells into mitochondrial metabolism and by inducing differentiation.