Glioblastoma Cells Require Glutamate Dehydrogenase to Survive Impairments of Glucose Metabolism or Akt Signaling

Abstract

Oncogenes influence nutrient metabolism and nutrient dependence. The oncogene c-Myc stimulates glutamine metabolism and renders cells dependent on glutamine to sustain viability (''glutamine addiction''), suggesting that treatments targeting glutamine metabolism might selectively kill c-Myc-transformed tumor cells. However, many current or proposed cancer therapies interfere with the metabolism of glucose, not glutamine. Here, we studied how c-Myc-transformed cells maintained viability when glucose metabolism was impaired. In SF188 glioblastoma cells, glucose deprivation did not affect net glutamine utilization but elicited a switch in the pathways used to deliver glutamine carbon to the tricarboxylic acid cycle, with a large increase in the activity of glutamate dehydrogenase (GDH). The effect on GDH resulted from the loss of glycolysis because it could be mimicked with the glycolytic inhibitor 2-deoxyglucose and reversed with a pyruvate analogue. Furthermore, inhibition of Akt signaling, which facilitates glycolysis, increased GDH activity whereas overexpression of Akt suppressed it, suggesting that Akt indirectly regulates GDH through its effects on glucose metabolism. Suppression of GDH activity with RNA interference or an inhibitor showed that the enzyme is dispensable in cells able to metabolize glucose but is required for cells to survive impairments of glycolysis brought about by glucose deprivation, 2-deoxyglucose, or Akt inhibition. Thus, inhibition of GDH converted these glutamine-addicted cells to glucose-addicted cells. The findings emphasize the integration of glucose metabolism, glutamine metabolism, and oncogenic signaling in glioblastoma cells and suggest that exploiting compensatory pathways of glutamine metabolism can improve the efficacy of cancer treatments that impair glucose utilization. [Cancer Res 2009;69(20):7986-93]

Sugar-free approaches to cancer cell killing

“…The amino acid glutamine can be incorporated into the mitochondrial Krebs cycle and can be used to generate fatty acids, nucleotides and energy. When deprived of glucose, glioblastoma cells have been shown to turn to glutamine utilization, and if glutamine metabolism is impaired, cells cannot survive in the absence of glucose (Yang et al, 2009). Thus, when glucose is not available, cells turn to amino acids and fatty acids to try to maintain energy levels and homeostatic functions.…”

Glutamine at focus: versatile roles in cancer

“…Moreover, glutamate can enter into mitochondria and be oxidized to α-ketoglutarate (α-KG), reducing NADP + to NADPH or NAD + to NADH and produces a second molecule of NH 4+ . This reaction is catalyzed by the glutamate dehydrogenase (GDH) which also plays a pivotal role in cancer survival [36]. GDH is the unique enzyme that can use NADP + or NAD + as cofactor.…”

“…In fact, some studies have shown unquestionable evidence that targeting glutamine metabolism, like blocking mitochondrial GLS1 activity, could be used to suppress tumor cell growth and transformation [36,46]. However, recent findings have suggested that even silencing GLS1 could suppress, but not eliminate, glioblastoma cell growth in vitro and in vivo.…”

“…Most recently, Yang et al have demonstrated that GLS and GDH generate NH 4+ from both γ-and α-nitrogens of glutamine, respectively. Studying glioblastoma cells with enhanced Myc activity through GC/MS techniques, the author reported that after 8 h, more than 90 % of the ammonia secreted in the medium was derived from both nitrogens [36]. But, later studies on tumor cells revealed that glutamine consumption/ammonia secretion ratio is about 75 % [33].…”

“…For example, aminooxyacetate (OAA), the nonspecific inhibitor of aminotransferase (TA) enzymes showed a cytostatic effect on proliferating breast cancer cell lines [154]. Furthermore, epigallocatechin gallate (EGCG), the inhibitor of GDH, demonstrated great efficacy to kill glutamine-addicted tumor cells when glucose was scarce [36]. In general, inhibitors that block glutaminolysis were sufficient to delayed tumor growth in a number of models, both in vitro and in vivo [36,48].…”