General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice.
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.
['Phillipson-Weiner|Lindsey|L|', 'Mirek|Emily T|ET|', 'Wang|Yongping|Y|', 'McAuliffe|W Geoffrey|WG|', 'Wek|Ronald C|RC|', 'Anthony|Tracy G|TG|0000-0002-8586-5884']
D061354:Acinar Cells D000818:Animals D001215:Asparaginase D001343:Autophagy D000091342:Endoplasmic Reticulum Chaperone BiP D059865:Endoplasmic Reticulum Stress D005260:Female D005346:Fibroblast Growth Factors D017353:Gene Deletion D006360:Heat-Shock Proteins D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D010179:Pancreas D010195:Pancreatitis D000073718:Pancreatitis-Associated Proteins D017346:Protein Serine-Threonine Kinases D056564:Sirtuin 1 D014157:Transcription Factors D014280:Triglycerides D014409:Tumor Necrosis Factor-alpha D000071717:X-Box Binding Protein 1 D019892:eIF-2 Kinase
eukaryotic initiation factor 2 protein kinase R-like ER kinase amino acid response endoplasmic reticulum stress unfolded protein response