Hypoxia and succinate antagonize 2-deoxyglucose effects on glioblastoma

Francesca Pistollato (1) , Sara Abbadi (1) , Elena Rampazzo (1) , Giampietro Viola (1) , Alessandro Della Puppa (2) , Lucia Cavallini (3) , Chiara Frasson (1) , Luca Persano (1) , David M. Panchision (4) , Giuseppe Basso (1)

1 Department of Pediatrics
2 Department of Neurosurgery
3 Department of Biochemistry
4 Division of Neuroscience and Basic Behavioral Science

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.

Mots clés: 2-deoxyglucose; Hypoxia; Hypoxia Inducible Factor-1α; proline hydroxylase 2; GBM differentiation.; GBM differentiation

Francesca Pistollato, Sara Abbadi, Elena Rampazzo, Giampietro Viola, Alessandro Della Puppa, et al.. Hypoxia and succinate antagonize 2-deoxyglucose effects on glioblastoma. Biochemical Pharmacology, 2010, 80 (10), pp.1517. ⟨10.1016/j.bcp.2010.08.003⟩. ⟨hal-00626232⟩