Interlude of cGMP and cGMP/protein kinase G type 1 in pancreatic adenocarcinoma cells.

Abstract

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. 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. 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. The cGMP and PKG signaling may be a target for developing new therapeutic approaches for PDAC.