Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells.
The idea that conversion of glucose to ATP is an attractive target for cancer therapy has been supported in part by the observation that glucose deprivation induces apoptosis in rodent cells transduced with the proto-oncogene MYC, but not in the parental line. Here, we found that depletion of glucose killed normal human cells irrespective of induced MYC activity and by a mechanism different from apoptosis. However, depletion of glutamine, another major nutrient consumed by cancer cells, induced apoptosis depending on MYC activity. This apoptosis was preceded by depletion of the Krebs cycle intermediates, was prevented by two Krebs cycle substrates, but was unrelated to ATP synthesis or several other reported consequences of glutamine starvation. Our results suggest that the fate of normal human cells should be considered in evaluating nutrient deprivation as a strategy for cancer therapy, and that understanding how glutamine metabolism is linked to cell viability might provide new approaches for treatment of cancer.
Yuneva
Mariia
M
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Zamboni
Nicola
N
Oefner
Peter
P
Sachidanandam
Ravi
R
Lazebnik
Yuri
Y
D017209:Apoptosis / Q000502:physiology*; D018929:Cell Culture Techniques; D002460:Cell Line; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000172:deficiency*; D006801:Humans; D008168:Lung / Q000166:cytology; D008297:Male; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D012867:Skin / Q000166:cytology; D014161:Transduction, Genetic
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine; D005947:Glucose