Nitric oxide/cyclic guanosine monophosphate inducers sodium nitroprusside and L-arginine inhibit the proliferation of gastric cancer cells via the activation of type II cyclic guanosine monophosphate-dependent protein kinase

Yao,Xiaoyuan; Wu,Yan; Zhu,Miaolin; Qian,Hai; Chen,Yongchang

doi:10.3892/ol.2015.3229

July-2015 Volume 10 Issue 1

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July-2015 Volume 10 Issue 1

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Article

Nitric oxide/cyclic guanosine monophosphate inducers sodium nitroprusside and L-arginine inhibit the proliferation of gastric cancer cells via the activation of type II cyclic guanosine monophosphate-dependent protein kinase

Authors:
- Xiaoyuan Yao
- Yan Wu
- Miaolin Zhu
- Hai Qian
- Yongchang Chen
View Affiliations / Copyright

Affiliations: Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
Pages: 479-484
|
Published online on: May 19, 2015

https://doi.org/10.3892/ol.2015.3229
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Abstract

Nitric oxide (NO) may activate soluble guanylyl cyclase (sGC), resulting in the increase of intracellular cyclic guanosine monophosphate (cGMP), a key molecule in the activation of type II cGMP‑dependent protein kinase (PKG II). In our previous study, the membrane‑permeable cGMP analogue 8‑pCPT‑cGMP was used to activate PKG II. The aim of the present study was to investigate whether NO/sGC‑induced endogenous cGMP is able to activate PKG II and induce the corresponding effects. In the AGS gastric cancer cell line, the expression of PKG II was increased by infecting the cells with an adenoviral construct encoding PKG II cDNA (Ad‑PKG II) and the activation of PKG II was induced by 8‑pCPT‑cGMP (positive control), the NO donor sodium nitroprusside (SNP) and the NO precursor L‑arginine. ELISA was performed to detect the concentration of cGMP in AGS cells and the Cell Counting Kit‑8 was used to analyze the proliferation of differently treated cells. Western blot analysis was used to detect the expression and phosphorylation of associated proteins. The results demonstrated that the level of cGMP was increased in cells treated with the NO donor or precursor. There was an obvious increase of ser239 phosphorylation of the vasodilator‑stimulated phosphoprotein, representing the increase in the activity of PKG II. The epidermal growth factor (EGF)‑induced proliferation of AGS cells was inhibited by infection with Ad‑PKG II and treatment with SNP or L‑arginine. In addition, EGF‑induced tyrosine phosphorylation of the EGF receptor (EGFR) and tyrosine/serine phosphorylation of extracellular signal‑regulated kinase (ERK) were also inhibited by infection with Ad‑PKG II and treatment with the NO donor or precursor. These data indicated that NO donors and precursors may activate the expression of PKG II, thereby blocking EGF‑initiated signaling of the mitogen‑activated protein kinase/ERK pathway and inhibiting EGF‑induced proliferative activity through preventing the phosphorylation of EGFR at Tyr1068.

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