Type II cGMP-dependent protein kinase inhibits ERK/JNK-mediated activation of transcription factors in gastric cancer cells.
A previous study has shown that type II cGMP?dependent protein kinase (PKG II) inhibits the proliferation of gastric cancer cells through blocking EGF-triggered MAPK/ERK signal transduction, indicating that the kinase may be a potential anticancer factor. In the present study, the role of PKG II in the EGF-induced activation of transcription ... factors in the MAPK/ERK signal transduction pathway was investigated. BGC-823 human gastric cancer cells were infected with adenoviral constructs encoding the cDNA of PKG II (pAd?PKG II) to increase the expression of PKG II and treated with 8-pCPT?cGMP to activate the enzyme. Using luciferase reporter assays, it was revealed that PKG II markedly suppressed the EGF-induced transcriptional activities of AP-1 and Elk1. Consistent with the inhibitory effect of PKG II on AP-1 activity, the expression levels of c-Jun and c-Fos, components of AP-1, were also inhibited. Co-immunoprecipitation analysis demonstrated that EGF treatment increased the AP-1 content through inducing the formation of p-c-Jun-c-Jun homodimers and p-c-Jun-c-Fos heterodimers. However, this combination was efficiently blocked by activated PKG II. While pretreatments with MAPK inhibitors suppressed the EGF-induced transcriptional activities of AP-1 and Elk1, PKG II prevented the EGF-induced phosphorylation/activation of ERK and JNK, but not the phosphorylation of p38MAPK induced by EGF. These data suggest that PKG II inhibits the EGF-triggered proliferation of gastric cancer cells through suppressing ERK-/JNK-, but not p38MAPK, -mediated AP-1 and Elk1 transactivation.
Mesh Terms:
Cell Line, Tumor, Cyclic GMP-Dependent Protein Kinase Type II, Epidermal Growth Factor, Extracellular Signal-Regulated MAP Kinases, Humans, Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Signal Transduction, Stomach Neoplasms, Transcription Factor AP-1, Transcription Factors, Transcriptional Activation, ets-Domain Protein Elk-1
Cell Line, Tumor, Cyclic GMP-Dependent Protein Kinase Type II, Epidermal Growth Factor, Extracellular Signal-Regulated MAP Kinases, Humans, Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Signal Transduction, Stomach Neoplasms, Transcription Factor AP-1, Transcription Factors, Transcriptional Activation, ets-Domain Protein Elk-1
Mol Med Rep
Date: Nov. 01, 2012
PubMed ID: 22940826
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