Interlude of cGMP and cGMP/protein kinase G type 1 in pancreatic adenocarcinoma cells.
OBJECTIVE
cAMP and cGMP signaling is important both for normal and cancer cells. This signaling is controlled by adenylyl and guanylyl cyclases and cyclic nucleotide phosphodiesterases. One of the direct targets for cGMP is protein kinase G (PKG). The main aim of this work was to investigate cGMP and PKG signaling in pancreatic adenocarcinoma (PDAC) cells.


METHODS
The PKG activity, cGMP, and calcium level were measured with the CycLex Cyclic GMP dependent protein kinase (cGK) Assay Kit, the DetectX Cyclic GMP Colorimetric EIA Kit, and the Fluo-4 NW Calcium Assay Kit, respectively. The Proteome Profiler Array was done using Human Phospho-Kinase Array and Human Phospho-MAPK Array Kits.


RESULTS
This study shows for the first time that functional PKG1 is expressed in PDAC cells. It demonstrates that the specific PKG1 inhibitor, DT3, induces cytotoxicity through necrosis and reduces proliferation and migration of PDAC cells. Moreover, ERK1/2 and p38 can be considered as potential targets for PKG1 in PDAC cells. In addition, the study shows that phosphodiesterases and nitric oxide-guanylyl cyclases regulate the cGMP level in PDAC cells, affecting the proliferation of the cells.


CONCLUSIONS
The cGMP and PKG signaling may be a target for developing new therapeutic approaches for PDAC.
From the *Department of General Surgery, University Hospital Heidelberg, Germany; and †Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
Svetlana
S
Karakhanova
Marina
M
Golovastova
Pavel P
PP
Philippov
Jens
J
Werner
Alexandr V
AV
Bazhin
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D010455:Peptides; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium