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.

Original languageEnglish (US)
Pages (from-to)7986-7993
Number of pages8
JournalCancer Research
Volume69
Issue number20
DOIs
StatePublished - Oct 15 2009

Fingerprint

Glutamate Dehydrogenase
Glioblastoma
Glutamine
Glucose
Glycolysis
Deoxyglucose
Food
Neoplasms
myc Genes
Citric Acid Cycle
Enzyme Inhibitors
RNA Interference
Pyruvic Acid
Oncogenes
Cell Survival
Carbon

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. / Chendong, Yang; Sudderth, Jessica; Tuyen, Dang; Bachoo, Robert G.; McDonald, Jeffrey G.; DeBerardinis, Ralph J.

In: Cancer Research, Vol. 69, No. 20, 15.10.2009, p. 7986-7993.

Research output: Contribution to journalArticle

@article{f656d6eed13c4c709d20df65d81c675e,
title = "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.",
author = "Yang Chendong and Jessica Sudderth and Dang Tuyen and Bachoo, {Robert G.} and McDonald, {Jeffrey G.} and DeBerardinis, {Ralph J.}",
year = "2009",
month = "10",
day = "15",
doi = "10.1158/0008-5472.CAN-09-2266",
language = "English (US)",
volume = "69",
pages = "7986--7993",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "20",

}

TY - JOUR

T1 - Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling

AU - Chendong, Yang

AU - Sudderth, Jessica

AU - Tuyen, Dang

AU - Bachoo, Robert G.

AU - McDonald, Jeffrey G.

AU - DeBerardinis, Ralph J.

PY - 2009/10/15

Y1 - 2009/10/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=70350217425&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350217425&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-09-2266

DO - 10.1158/0008-5472.CAN-09-2266

M3 - Article

C2 - 19826036

AN - SCOPUS:70350217425

VL - 69

SP - 7986

EP - 7993

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 20

ER -