Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice

Cancers

卷:14

Michael Leitges¹  Nicole R. Murray²  Yi Liu²  Kristin S. Inman²  Alan P. Fields²  Michele L. Scotti Buzhardt²  Howard C. Crawford²  Murli Krishna³ 

[1] Department of BioMedical Sciences, Faculty of Medicine, Memorial University, St. John’s, NL A1M 2V7, Canada;

[2] Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA;

[3] Department of Pathology/Lab Medicine, Mayo Clinic, Jacksonville, FL 32224, USA;

关键词: pancreatic cancer;    tumor progression;    protein kinase C iota;    autophagy;    immune cell infiltration;   

DOI  :  10.3390/cancers14030796

来源: DOAJ

【 摘 要 】

Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for Kras^G12D-mediated lung cancer initiation and progression. PKCι expression is required for pancreatic cancer cell growth and maintenance of the transformed phenotype; however, nothing is known about the role of PKCι in pancreas development or pancreatic tumorigenesis. In this study, we investigated the effect of pancreas-specific ablation of PKCι expression on pancreatic cellular homeostasis, susceptibility to pancreatitis, and Kras^G12D-mediated pancreatic cancer development. Knockout of pancreatic Prkci significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to caerulein-induced pancreatitis. Prkci-ablated pancreatic acinar cells exhibited P62 aggregation and a loss of autophagic vesicles. Loss of pancreatic Prkci promoted Kras^G12D-mediated pancreatic intraepithelial neoplasia formation but blocked progression to adenocarcinoma, consistent with disruption of autophagy. Our results reveal a novel promotive role for PKCι in pancreatic epithelial cell autophagy and pancreatic cancer progression.

【 授权许可】

Unknown