Hypoxia and succinate antagonize 2-deoxyglucose effects on glioblastoma.
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.
Pistollato
Francesca
F
Hemato-Oncology Laboratory, Department of Pediatrics, University of Padova, Via Giustiniani 3, Padova 35128, Italy.
Abbadi
Sara
S
Rampazzo
Elena
E
Viola
Giampietro
G
Della Puppa
Alessandro
A
Cavallini
Lucia
L
Frasson
Chiara
C
Persano
Luca
L
Panchision
David M
DM
Basso
Giuseppe
G
D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D003847:Deoxyglucose / Q000494:pharmacology*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013385:Succinate Dehydrogenase / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism* / Q000494:pharmacology
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D003847:Deoxyglucose; D019802:Succinic Acid; D013385:Succinate Dehydrogenase; D005978:Glutathione; D010100:Oxygen