Glucose Deprivation Induces ATF4-Mediated Apoptosis through TRAIL Death Receptors

Mol Cell Biol. 2017 May 2;37(10):e00479-16. doi: 10.1128/MCB.00479-16. Print 2017 May 15.


Metabolic stress occurs frequently in tumors and in normal tissues undergoing transient ischemia. Nutrient deprivation triggers, among many potential cell death-inducing pathways, an endoplasmic reticulum (ER) stress response with the induction of the integrated stress response transcription factor ATF4. However, how this results in cell death remains unknown. Here we show that glucose deprivation triggered ER stress and induced the unfolded protein response transcription factors ATF4 and CHOP. This was associated with the nontranscriptional accumulation of TRAIL receptor 1 (TRAIL-R1) (DR4) and with the ATF4-mediated, CHOP-independent induction of TRAIL-R2 (DR5), suggesting that cell death in this context may involve death receptor signaling. Consistent with this, the ablation of TRAIL-R1, TRAIL-R2, FADD, Bid, and caspase-8 attenuated cell death, although the downregulation of TRAIL did not, suggesting ligand-independent activation of TRAIL receptors. These data indicate that stress triggered by glucose deprivation promotes the ATF4-dependent upregulation of TRAIL-R2/DR5 and TRAIL receptor-mediated cell death.

Keywords: ATF4; TRAIL; apoptosis; cancer metabolism; glucose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism*
  • Apoptosis*
  • Endoplasmic Reticulum Stress*
  • Gene Expression Regulation, Neoplastic
  • Glucose / deficiency*
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Transcription Factor CHOP / metabolism


  • DDIT3 protein, human
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • Glucose