Rebamipide-induced downregulation of phospholipase D inhibits inflammation and proliferation in gastric cancer cells

Dong Woo Kang,Do Sik Min,Do Yoon Park,Ki Whan Hong,Gyesik Min

doi:10.3858/emm.2010.42.8.056

Dong Woo Kang, Do Sik Min + Show 3 more

Open Access

https://doi.org/10.3858/emm.2010.42.8.056

Copy DOI

Abstract

Rebamipide a gastroprotective drug, is clinically used for the treatment of gastric ulcers and gastritis, but its actions on gastric cancer are not clearly understood. Phospholipase D (PLD) is overexpressed in various types of cancer tissues and has been implicated as a critical factor in inflammation and carcinogenesis. However, whether rebamipide is involved in the regulation of PLD in gastric cancer cells is not known. In this study, we showed that rebamipide significantly suppressed the expression of both PLD1 and PLD2 at a transcriptional level in AGS and MKN-1 gastric cancer cells. Downregulation of PLD expression by rebamipide inhibited its enzymatic activity. In addition, rebamipide inhibited the transactivation of nuclear factor kappa B (NFkappaB), which increased PLD1 expression. Rebamipide or PLD knockdown significantly suppressed the expression of genes involved in inflammation and proliferation and inhibited the proliferation of gastric cancer cells. In conclusion, rebamipide-induced downregulation of PLD may contribute to the inhibition of inflammation and proliferation in gastric cancer.

Highlights

Rebamipide (2-[4-chlorobenzoylamino]-3-[2(1H)quinolinon-4-yl]propionic acid; OPC-12759) is a mucosal protective agent used for the treatment of gastritis and gastric ulcer (Arakawa et al, 1998)
To further confirm whether rebamipide-induced Phospholipase D (PLD) suppression is regulated at the transcriptional level, AGS or MKN-1 gastric cancer cells were transiently transfected with PLD1- or PLD2-luciferase reporter constructs and treated with rebamipide
Dose and time kinetics of rebamipide-induced suppression of the PLD1 protein showed a pattern similar to that of the transcriptional expression. These results suggest that the expression of PLD isozymes was downregulated by rebamipide at both transcriptional and posttranscriptional levels

Summary

Introduction

Rebamipide (2-[4-chlorobenzoylamino]-3-[2(1H)quinolinon-4-yl]propionic acid; OPC-12759) is a mucosal protective agent used for the treatment of gastritis and gastric ulcer (Arakawa et al, 1998). Rebamipide has been reported to act as an anti-inflammatory agent in both acute and chronic inflammation and has an inhibitory effect on proinflammatory cytokines (McCarthy et al, 2003) It exerts protective effect against gastric mucosal inflammation induced by Helicobacter pylori by inhibiting neutrophil function (Yoshida et al, 1996; Aihara et al, 1998; Arakawa et al, 2005). Rebamipide has been reported to inhibit the growth of gastric cancer cells (Tarnawski et al, 2005; Tanigawa et al, 2007) and prevent dextran sulfate sodium-induced colitis in rats (Kishimoto et al, 2000). These studies shed some light on the actions of rebamipide, the exact targets and molecular mechanism of action of rebamipide in cancer cells are still unknown

Methods

Results

Conclusion