title: General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice.
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.
authors.affiliation: Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey;
authors.forename: Lindsey
authors.initials: L
authors.lastname: Phillipson-Weiner
authors.affiliation: Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey;
authors.forename: Emily T
authors.initials: ET
authors.lastname: Mirek
authors.affiliation: Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey;
authors.forename: Yongping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and.
authors.forename: W Geoffrey
authors.initials: WG
authors.lastname: McAuliffe
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
authors.affiliation: Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; New Jersey Institute for Food, Nutrition, and Health, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; tracy.anthony@rutgers.edu.
authors.forename: Tracy G
authors.identifier: 0000-0002-8586-5884
authors.initials: TG
authors.lastname: Anthony
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001215:Asparaginase / Q000633:toxicity; D001343:Autophagy; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D010195:Pancreatitis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D001215:Asparaginase; D000091342:Endoplasmic Reticulum Chaperone BiP; D005346:Fibroblast Growth Factors; D006360:Heat-Shock Proteins; 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; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C000612141:REG3A protein, human; C000605544:Xbp1 protein, mouse; C414620:fibroblast growth factor 21; C070634:Eif2ak4 protein, mouse; C470545:Sirt1 protein, mouse
keywords: amino acid response; endoplasmic reticulum stress; eukaryotic initiation factor 2; protein kinase R-like ER kinase; unfolded protein response