title: Anti-tumor properties of the cGMP/protein kinase G inhibitor DT3 in pancreatic adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Therefore, new therapeutic options are urgently needed to improve the survival of PDAC patients. Protein kinase G (PKG) conducts the interlude of cGMP signaling which is important for healthy as well as for cancer cells. DT3 is a specific inhibitor of PKG, and it has been shown to possess an anti-tumor cytotoxic activity in vitro. The main aim of this work was to investigate anti-tumor effects of DT3 upon PDAC in vivo.Expression of PKG was assessed with real-time PCR analysis in the normal and tumor pancreatic cells. In vitro cell viability, proliferation, apoptosis, necrosis, migration, and invasion of the murine PDAC cell line Panc02 were assessed after DT3 treatment. In vivo anti-tumor effects of DT3 were investigated in the murine Panc02 orthotopic model of PDAC. Western blot analysis was used to determine the phosphorylation state of the proteins of interest.Functional PKGI is preferentially expressed in PDAC cells. DT3 was capable to reduce viability, proliferation, and migration of murine PDAC cells in vitro. At the same time, DT3 treatment did not change the viability of normal epithelial cells of murine liver. In vivo, DT3 treatment reduced the tumor volume and metastases in PDAC-bearing mice, but it was ineffective to prolong the survival of the tumor-bearing animals. In addition, DT3 treatment decreased phosphorylation of GSK-3, P38, and CREB in murine PDAC.Inhibition of PKG could be a potential therapeutic strategy for PDAC treatment which should be carefully validated in future pre-clinical studies.
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg,, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Soltek
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg,, Germany.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Karakhanova
authors.affiliation: Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Golovastova
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich,, Germany.
authors.forename: Jan G
authors.initials: JG
authors.lastname: D'Haese
authors.affiliation: Department of General Surgery, University Hospital Heidelberg, Heidelberg,, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Serba
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich,, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Nachtigall
authors.affiliation: Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Pavel P
authors.initials: PP
authors.lastname: Philippov
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich,, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Werner
authors.affiliation: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich,, Germany. alexandr.bazhin@med.uni-muenchen.de.
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Bazhin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006152:Cyclic GMP / Q000037:antagonists & inhibitors*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C556898:DT-3 peptide; D010455:Peptides; D047428:Protein Kinase Inhibitors; D017869:Cyclic GMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D006152:Cyclic GMP
keywords: DT3; Orthotopic mouse model; Panc02; Pancreatic adenocarcinoma; Protein kinase G