Treatment with the anti-leukemic agent asparaginase can induce acute pancreatitis but the pathophysiology remains obscure. In the liver of mice, the eIF2 kinase GCN2 is essential for mitigating metabolic stress caused by asparaginase. Herein we determined the consequences of asparaginase treatment on the pancreata of mice with GCN2 intact (WT) or deleted (ΔGcn2). Mean pancreas weights in ΔGcn2 mice treated with asparaginase for 8 d 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 contributing 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 pancreas exposed to asparaginase induced ER stress, there was increased phosphorylation of PERK and its substrate eIF2 in the pancreas of asparaginase-treated ΔGcn2 mice. In addition, mRNA expression of PERK-target genes, Atf4, Atf3, Atf6, Fgf21, Hspa5 and sXbp1, were elevated in the pancreas of asparaginase-treated ΔGcn2 mice accompanied by increased pancreas mass. Furthermore, genetic markers of oxidative stress (Sirt1), inflammation (Tnfα) and pancreatic injury (Pap) were elevated in asparaginase-treated ΔGcn2 but not WT mice. These data indicate that loss of GCN2 predisposes the exocrine pancreas toward a maladaptive ER stress response and autophagy during asparaginase treatment, and represent a genetic basis for development of asparaginase-associated pancreatitis.
- amino acid response
- ER stress
- Copyright © 2016, American Journal of Physiology- Gastrointestinal and Liver Physiology