Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling.
Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling.
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DOI：
10.1158/0008-5472.can-09-2266
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发表时间：
2009-10-15
期刊：
影响因子：
11.2
通讯作者：
DeBerardinis RJ
中科院分区：
文献类型：
--
作者：
Yang C;Sudderth J;Dang T;Bachoo RM;McDonald JG;DeBerardinis RJ
癌基因影响营养代谢和营养依赖。癌基因c-Myc刺激谷氨酰胺代谢，并使细胞依赖于谷氨酰胺来维持生存力（“谷氨酰胺成瘾”），这表明靶向谷氨酰胺代谢的治疗可能选择性地杀死c-Myc转化的肿瘤细胞。然而，许多目前或提出的癌症疗法干扰葡萄糖的代谢，而不是谷氨酰胺。在这里，我们研究了c-Myc转化的细胞如何在葡萄糖代谢受损时保持活力。在SF 188胶质母细胞瘤细胞中，葡萄糖剥夺不影响净谷氨酰胺利用率，但引起用于将谷氨酰胺碳传递到三羧酸循环的途径的切换，谷氨酸脱氢酶（GDH）的活性大幅增加。对GDH的影响是由于糖酵解的损失，因为它可以用糖酵解抑制剂2-脱氧葡萄糖模拟，并用丙酮酸类似物逆转。此外，抑制Akt信号，促进糖酵解，增加GDH活性和Akt的过表达抑制它，这表明Akt通过其对葡萄糖代谢的影响间接调节GDH。用RNA干扰或抑制剂抑制GDH活性表明，该酶在能够代谢葡萄糖的细胞中被抑制，但对于细胞存活由葡萄糖剥夺、2-脱氧葡萄糖或Akt抑制引起的糖酵解损伤是必需的。因此，GDH的抑制将这些谷氨酰胺成瘾细胞转化为葡萄糖成瘾。这些发现强调了胶质母细胞瘤细胞中葡萄糖代谢、谷氨酰胺代谢和致癌信号的整合，并表明利用谷氨酰胺代谢的代偿途径可以提高损害葡萄糖利用的癌症治疗的疗效。
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 analog. Furthermore, inhibition of Akt signaling, which facilitates glycolysis, increased GDH activity and over-expression 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 addiction. 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.