General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice

Lindsey Phillipson-Weiner, Emily T. Mirek, Yongping Wang, W. Geoffrey McAuliffe, Ronald Wek, Tracy G. Anthony

Research output: Contribution to journalArticle

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Abstract

Treatment with the antileukemic agent asparaginase can induce acute pancreatitis, but the pathophysiology remains obscure. In the liver of mice, eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2) is essential for mitigating metabolic stress caused by asparaginase. We determined the consequences of asparaginase treatment on the pancreata of wild-type (WT, GCN2-intact) and GCN2-deleted (ΔGcn2) mice. Mean pancreas weights in ΔGcn2 mice treated with asparaginase for 8 days were increased (P < 0.05) above all other groups. Histological examination revealed acinar cell swelling and altered staining of zymogen granules in ΔGcn2, but not WT, mice. Oil Red O staining and measurement of pancreas triglycerides excluded lipid accumulation as a contributor to acini appearance. Instead, transmission electron microscopy revealed dilatation of the endoplasmic reticulum (ER) and accumulation of autophagic vacuoles in the pancreas of ΔGcn2 mice treated with asparaginase. Consistent with the idea that loss of GCN2 in a pancreas exposed to asparaginase induced ER stress, phosphorylation of protein kinase R-like ER kinase (PERK) and its substrate eIF2 was increased in the pancreas of asparaginase-treated ΔGcn2 mice. In addition, mRNA expression of PERK target genes, activating transcription factors 4, 3, and 6 (Atf4, Atf3, and Atf6), fibroblast growth factor 21 (Fgf21), heat shock 70-kDa protein 5 (Hspa5), and spliced Xbp1 (sXbp1), as well as pancreas mass, was elevated in the pancreas of asparaginase-treated ΔGcn2 mice. Furthermore, genetic markers of oxidative stress [sirtuin (Sirt1)], inflammation [tumor necrosis factor-α (Tnfα)], and pancreatic injury [pancreatitis-associated protein (Pap)] were elevated in asparaginase-treated ΔGcn2, but not WT, mice. These data indicate that loss of GCN2 predisposes the exocrine pancreas to a maladaptive ER stress response and autophagy during asparaginase treatment and represent a genetic basis for development of asparaginase-associated pancreatitis.

Original languageEnglish (US)
Pages (from-to)G1061-G1070
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume310
Issue number11
DOIs
StatePublished - Jun 1 2016

Fingerprint

Asparaginase
Pancreatitis
Pancreas
Eukaryotic Initiation Factor-2
Endoplasmic Reticulum Stress
Endoplasmic Reticulum
Activating Transcription Factor 6
Activating Transcription Factor 4
Activating Transcription Factor 3
Staining and Labeling
Exocrine Pancreas
Physiological Stress
HSP70 Heat-Shock Proteins
Acinar Cells
Autophagy
Secretory Vesicles
Heat-Shock Proteins
Vacuoles
Transmission Electron Microscopy
Genetic Markers

Keywords

  • Amino acid response
  • Endoplasmic reticulum stress
  • Eukaryotic initiation factor 2
  • Protein kinase R-like ER kinase
  • Unfolded protein response

ASJC Scopus subject areas

  • Physiology
  • Medicine(all)
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice. / Phillipson-Weiner, Lindsey; Mirek, Emily T.; Wang, Yongping; McAuliffe, W. Geoffrey; Wek, Ronald; Anthony, Tracy G.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 310, No. 11, 01.06.2016, p. G1061-G1070.

Research output: Contribution to journalArticle

Phillipson-Weiner, Lindsey ; Mirek, Emily T. ; Wang, Yongping ; McAuliffe, W. Geoffrey ; Wek, Ronald ; Anthony, Tracy G. / General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2016 ; Vol. 310, No. 11. pp. G1061-G1070.
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