title: Genetic inhibition of protein kinase Cε attenuates necrosis in experimental pancreatitis.
abstract: Understanding the regulation of death pathways, necrosis and apoptosis, in pancreatitis is important for developing therapies directed to the molecular pathogenesis of the disease. Protein kinase Cε (PKCε) has been previously shown to regulate inflammatory responses and zymogen activation in pancreatitis. Furthermore, we demonstrated that ethanol specifically activated PKCε in pancreatic acinar cells and that PKCε mediated the sensitizing effects of ethanol on inflammatory response in pancreatitis. Here we investigated the role of PKCε in the regulation of death pathways in pancreatitis. We found that genetic deletion of PKCε resulted in decreased necrosis and severity in the in vivo cerulein-induced pancreatitis and that inhibition of PKCε protected the acinar cells from CCK-8 hyperstimulation-induced necrosis and ATP reduction. These findings were associated with upregulation of mitochondrial Bak and Bcl-2/Bcl-xL, proapoptotic and prosurvival members in the Bcl-2 family, respectively, as well as increased mitochondrial cytochrome c release, caspase activation, and apoptosis in pancreatitis in PKCε knockout mice. We further confirmed that cerulein pancreatitis induced a dramatic mitochondrial translocation of PKCε, suggesting that PKCε regulated necrosis in pancreatitis via mechanisms involving mitochondria. Finally, we showed that PKCε deletion downregulated inhibitors of apoptosis proteins, c-IAP2, survivin, and c-FLIPs while promoting cleavage/inactivation of receptor-interacting protein kinase (RIP). Taken together, our findings provide evidence that PKCε activation during pancreatitis promotes necrosis through mechanisms involving mitochondrial proapoptotic and prosurvival Bcl-2 family proteins and upregulation of nonmitochondrial pathways that inhibit caspase activation and RIP cleavage/inactivation. Thus PKCε is a potential target for prevention and/or treatment of acute pancreatitis.
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, and South California Research Center for Alcoholic Liver and Pancreatic Diseases, California; Beijing Hospital, Beijing, China.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, and South California Research Center for Alcoholic Liver and Pancreatic Diseases, California; jzyuan@ucla.edu.
authors.forename: Jingzhen
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, and South California Research Center for Alcoholic Liver and Pancreatic Diseases, California; St. George's University School of Medicine, St. George's, Grenada; and.
authors.forename: Tanya
authors.initials: T
authors.lastname: Tan
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, and South California Research Center for Alcoholic Liver and Pancreatic Diseases, California; Beijing Hospital, Beijing, China.
authors.forename: Wenzhuo
authors.initials: W
authors.lastname: Jia
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, and South California Research Center for Alcoholic Liver and Pancreatic Diseases, California; Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Lugea
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, and South California Research Center for Alcoholic Liver and Pancreatic Diseases, California;
authors.forename: Olga
authors.initials: O
authors.lastname: Mareninova
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, and South California Research Center for Alcoholic Liver and Pancreatic Diseases, California; Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Waldron
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, and South California Research Center for Alcoholic Liver and Pancreatic Diseases, California; Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D002108:Ceruletide / Q000633:toxicity; D045304:Cytochromes c / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D017353:Gene Deletion; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D012844:Sincalide / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D000431:Ethanol; D002108:Ceruletide; D045304:Cytochromes c; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D051744:Protein Kinase C-epsilon; D012844:Sincalide
keywords: apoptosis; inhibitors of apoptotic proteins (IAPs), Bcl-2 family proteins; necrosis; receptor-interacting protein kinase (RIP)