Glioblastoma-Derived Cells Exhibit Differential Responses To Glycolysis Inhibition Under Hypoxia

e13031 It has been suggested that oxygen tension is a crucial component of the brain tumor niche, as hypoxia positively correlates with tumor aggressiveness and over-activity of hypoxia inducible factor-1α (HIF-1α) reinforces tumor progression. Furthermore, hypoxia has been implicated in the regulation of several signaling pathways (Notch, BMP), angiogenesis and importantly, glucose metabolism. Here we investigate the effects mediated by in vitro glycolysis inhibition by using 2-deoxyglucose (2-DG) in glioblastoma (GBM) derived cells maintained under two different oxygen tensions, a lowered oxygen tension (2%) versus a higher non-physiological (20%). GBM account for 50% of all gliomas and arise after age 50 in most patients and it has been seen that younger patients tend to have a better prognosis than the elderly. Our results show that adult GBM displaying a highly immature phenotype manifested the highest resistance to glucose deprivation. Furthermore, increase of multi-drug resistant cell fraction, described as side population, occurred following 2-DG treatment, but only under hypoxia. Neuronal committed precursors were selected by 2-DG, but these effects were mitigated by hypoxia. Also, hypoxia inhibits the mitochondria-controlled apoptosis induced by 2-DG, by conferring cell resistance through progressive activation of pro-survival NF-kB and induction of tumor cell autophagy. Importantly, HIF-1α level reduction and proline hydroxylase 2 (PHD2) upregulation occurred following 2-DG treatment even under hypoxia, and this may depend on reactive oxygen species reduction. These results indicate differences in tumor cells behavior that may be predictive of cell response to therapy aiming to limit glucose uptake or glucose metabolism. No significant financial relationships to disclose.