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

Gabriel J. Wilson, Piyawan Bunpo, Judy K. Cundiff, Ronald Wek, Tracy G. Anthony

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume305
Issue number9
DOIs
StatePublished - Nov 1 2013

Fingerprint

Eukaryotic Initiation Factor-2
Asparaginase
Phosphotransferases
Amino Acids
Liver
Asparagine
Therapeutics
Glutamine
DNA Damage
Oxidative Stress
Activating Transcription Factor 4
Aspartate-Ammonia Ligase
Phosphorylation
CCAAT-Enhancer-Binding Proteins
Excipients
Sirolimus
Glutathione Peroxidase
Genetic Markers
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Carrier Proteins

Keywords

  • Amino acid stress response
  • Endoplasmic reticulum stress
  • Eukaryotic initiation factor 2
  • Liver
  • Steatosis

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

The eukaryotic initiation factor 2 kinase GCN2 protects against hepatotoxicity during asparaginase treatment. / Wilson, Gabriel J.; Bunpo, Piyawan; Cundiff, Judy K.; Wek, Ronald; Anthony, Tracy G.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 305, No. 9, 01.11.2013.

Research output: Contribution to journalArticle

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