Type II cGMP‑dependent protein kinase inhibits EGF‑induced JAK/STAT signaling in gastric cancer cells.

Abstract

Previous research has demonstrated that type II cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG II) inhibited epidermal growth factor (EGF)‑initiated signal transduction of MAPK‑mediated, PI3K/Akt‑mediated and PLCγ1‑mediated pathways through blocking EGF‑induced phosphorylation/activation of EGF receptor (EGFR). As EGF/EGFR signaling also initiated signal transduction of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)‑mediated pathway, the present study was performed to investigate whether PKG II exerts an inhibitory effect this pathway. AGS human gastric cancer cell line was infected with adenoviral constructs encoding the cDNA of PKG II (Ad‑PKG II), to increase the expression of PKG II, and treated with 8‑pCPT‑cGMP to activate the kinase. Western blotting was performed to detect the phosphorylation/activation of EGFR, JAK1, JAK2, STAT1 and STAT3 and the expression of cell cycle‑associated proteins, including cyclin D1 and cyclin E. EGF‑induced cell cycle changes were detected by flow cytometry. Transcriptional activity was determined by a reporter gene assay. The results demonstrated that EGF treatment increased the phosphorylation of EGFR, JAK1, JAK2, STAT1 and STAT3, increased the expression levels of cyclin D1 and cyclin E, promoted the cells to enter S phase, and stimulated transcriptional activity in the cells. Increased PKG II activity through infecting the cells with Ad‑PKG II and activating the kinase with 8‑pCPT‑cGMP efficiently reversed the changes caused by EGF. The results suggest that PKG II inhibits EGF‑induced signal transduction of the JAK/STAT‑mediated pathway and further confirms that PKG II may be a cancer inhibitor.

• Authors: Min Wu, Yan Wu, Ting Lan, Lu Jiang, Hai Qian, Yongchang Chen
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 14 Issue 2 Pg. 1849-56 (Aug 2016) ISSN: 1791-3004 [Electronic] Greece
• PMID: 27357186 (Publication Type: Journal Article)

Chemical References

• Cyclin E
• STAT Transcription Factors
• STAT1 Transcription Factor
• STAT3 Transcription Factor
• Cyclin D1
• Epidermal Growth Factor
• ErbB Receptors
• Janus Kinase 1
• Janus Kinase 2
• Janus Kinases
• Cyclic GMP-Dependent Protein Kinase Type II

Topics

• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cyclic GMP-Dependent Protein Kinase Type II (metabolism)
• Cyclin D1 (genetics, metabolism)
• Cyclin E (genetics, metabolism)
• Epidermal Growth Factor (metabolism, pharmacology)
• ErbB Receptors (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Janus Kinase 1 (metabolism)
• Janus Kinase 2 (metabolism)
• Janus Kinases (metabolism)
• Phosphorylation
• STAT Transcription Factors (metabolism)
• STAT1 Transcription Factor (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Stomach Neoplasms (metabolism)
• Transcriptional Activation (drug effects)