期刊
BIOCHEMICAL PHARMACOLOGY
卷 80, 期 10, 页码 1517-1527出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2010.08.003
关键词
2-Deoxyglucose; Hypoxia; Hypoxia inducible factor-1 alpha; Prolyl hydroxylase 2; GBM differentiation
资金
- Italian Association for the Fight against Neuroblastoma
- Italian Association AIRC
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-1 alpha (HIF-1 alpha) degradation occurs and this induces GBM cells to acquire a neuronal committed phenotype. By adding succinate these effects are reverted, as succinate stabilizes HIF-1 alpha 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. (c) 2010 Elsevier Inc. All rights reserved.
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