ATF4 mediates necrosis induced by glucose deprivation and apoptosis induced by 2-deoxyglucose in the same cells

FEBS J. 2015 Sep;282(18):3647-58. doi: 10.1111/febs.13369. Epub 2015 Aug 1.


Altered metabolism is a hallmark of cancer that opens new therapeutic possibilities. 2-deoxyglucose (2-DG) is a non-metabolizable glucose analog tested in clinical trials and is frequently used in experimental settings to mimic glucose starvation. However, in the present study, conducted in a rhabdomyosarcoma cell line, we find that 2-DG induces classical nuclear apoptotic morphology and caspase-dependent cell death, whereas glucose deprivation drives cells toward necrotic cell death. Necrosis induced by glucose deprivation did not resemble necroptosis or ferroptosis and was not prevented by antioxidants. Both stimuli promote endoplasmic reticulum stress. Moreover, the transcription factor ATF4 is found to mediate both the apoptosis induced by 2-DG and the glycosylation inhibitor tunicamycin, as well as the necrosis provoked by glucose withdrawal. Several hexoses partially prevented glucose deprivation-induced necrosis in rhabdomyosarcoma, although only mannose prevented apoptosis induced by 2-DG. In both cases, a reduction of cell death was associated with decreased levels of ATF4. Our results confirm previous data indicating the differential effects of these two forms with respect to inhibiting glucose metabolism, and they place endoplasmic reticulum stress as the critical mediator of glucose starvation-induced cell death.

Keywords: ER stress; apoptosis; cancer metabolism; glucose; rhabdomyosarcoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / antagonists & inhibitors
  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Apoptosis / drug effects*
  • Apoptosis / physiology*
  • Cell Line, Tumor
  • Deoxyglucose / metabolism
  • Deoxyglucose / pharmacology*
  • Endoplasmic Reticulum Stress / drug effects
  • Glucose / deficiency*
  • Glucose / metabolism
  • Glycolysis / drug effects
  • Humans
  • Monosaccharides / metabolism
  • Monosaccharides / pharmacology
  • Necrosis
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / genetics
  • Rhabdomyosarcoma / drug therapy
  • Rhabdomyosarcoma / metabolism
  • Rhabdomyosarcoma / pathology
  • Tunicamycin / pharmacology


  • ATF4 protein, human
  • Monosaccharides
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Tunicamycin
  • Activating Transcription Factor 4
  • Deoxyglucose
  • Glucose