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Glucose Deprivation Induces ATF4-Mediated Apoptosis through TRAIL Death Receptors

Raffaella Iurlaro1, Franziska Püschel1, Clara Lucía León-Annicchiarico1

  • 1Cell Death Regulation Group, Molecular Mechanisms and Experimental Therapy in Oncology Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

Molecular and Cellular Biology
|March 1, 2017
PubMed

Insights

Nutrient deprivation induces endoplasmic reticulum (ER) stress and activates ATF4. This leads to TRAIL receptor-mediated cell death, revealing a new pathway for cell death during metabolic stress.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Cancer biology

Background:

  • Metabolic stress, common in tumors and ischemic tissues, triggers endoplasmic reticulum (ER) stress.
  • The integrated stress response transcription factor ATF4 is induced during ER stress, but its role in cell death is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which glucose deprivation-induced ER stress leads to cell death.
  • To investigate the involvement of death receptor signaling pathways in this process.

Main Methods:

  • Induction of ER stress via glucose deprivation in cellular models.
  • Analysis of ATF4, CHOP, and TRAIL receptor expression.
  • Assessment of cell death pathways, including TRAIL receptor signaling components (TRAIL-R1, TRAIL-R2, FADD, Bid, caspase-8).
  • Genetic ablation and downregulation techniques to study pathway contributions.

Main Results:

  • Glucose deprivation induced ER stress and activated ATF4 and CHOP.
  • Nontranscriptional accumulation of TRAIL-R1 (DR4) and ATF4-mediated, CHOP-independent induction of TRAIL-R2 (DR5) were observed.
  • Ablation of TRAIL-R1, TRAIL-R2, FADD, Bid, and caspase-8 attenuated cell death, indicating involvement of the death receptor pathway.
  • Ligand-independent activation of TRAIL receptors was suggested by the lack of effect upon TRAIL downregulation.

Conclusions:

  • Glucose deprivation-induced metabolic stress promotes ATF4-dependent upregulation of TRAIL-R2/DR5.
  • TRAIL receptor-mediated signaling is a key pathway for cell death under these stress conditions.
  • This identifies a novel mechanism linking metabolic stress, ER stress, and programmed cell death.
Keywords:
ATF4TRAILapoptosiscancer metabolismglucose

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