The eukaryotic initiation factor 2 kinase GCN2 protects against hepatotoxicity during asparaginase treatment

Am J Physiol Endocrinol Metab. 2013 Nov 1;305(9):E1124-33. doi: 10.1152/ajpendo.00080.2013. Epub 2013 Sep 3.

Abstract

Asparaginase is an important drug in the treatment regimen for acute lymphoblastic leukemia. Asparaginase depletes circulating asparagine and glutamine, activating an amino acid stress response (AAR) involving phosphorylation of eukaryotic initiation factor 2 (eIF2) by general control nonderepressible kinase 2 (GCN2). We hypothesized that GCN2 functions to mitigate hepatic stress during asparaginase therapy by activating the AAR. To test this idea, C57BL/6J wild-type mice (Gcn2(+/+)) and those deleted for Gcn2 (Gcn2(-/-)) were injected with asparaginase or saline excipient one time daily for 1 or 6 days. In liver, increased phosphorylation of eIF2 and mRNA expression of AAR target genes activating transcription factor 4, asparagine synthetase, eIF4E-binding protein 1, and CAAT enhancer-binding protein homologous protein were significantly blunted or blocked in the liver of Gcn2(-/-) mice. Loss of AAR during asparaginase coincided with increases in mammalian target of rapamycin signaling, hepatic triglyceride accumulation, and DNA damage in association with genetic markers of oxidative stress (glutathione peroxidase) and inflammation (tumor necrosis factor alpha-α). Although asparaginase depleted circulating asparagine in both Gcn2(+/+) and Gcn2(-/-) mice, all other amino acids, including plasma glutamine, were elevated in the plasma of Gcn2(-/-) mice. This study shows that loss of GCN2 promotes oxidative stress and inflammatory-mediated DNA damage during asparaginase therapy, suggesting that patients with reduced or dysfunctional AAR may be at risk of developing hepatic complications during asparaginase treatment.

Keywords: amino acid stress response; endoplasmic reticulum stress; eukaryotic initiation factor 2; liver; steatosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / blood
  • Animals
  • Antineoplastic Agents / antagonists & inhibitors*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents / toxicity*
  • Asparaginase / antagonists & inhibitors*
  • Asparaginase / therapeutic use
  • Asparaginase / toxicity*
  • Blotting, Western
  • Body Weight / genetics
  • Body Weight / physiology
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • DNA Damage
  • Eating / genetics
  • Eating / physiology
  • Endoplasmic Reticulum Stress / drug effects
  • Female
  • Inflammation / physiopathology
  • Liver / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / physiology
  • Organ Size / genetics
  • Organ Size / physiology
  • Protein-Serine-Threonine Kinases / pharmacology*
  • Real-Time Polymerase Chain Reaction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / physiology
  • Triglycerides / metabolism
  • Unfolded Protein Response / drug effects
  • Unfolded Protein Response / genetics

Substances

  • Amino Acids
  • Antineoplastic Agents
  • Multiprotein Complexes
  • Triglycerides
  • TOR Serine-Threonine Kinases
  • Eif2ak4 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • Asparaginase