Rebamipide abolishes Helicobacter pylori CagA-induced phospholipase D1 expression via inhibition of NFκB and suppresses invasion of gastric cancer cells.
Infection with cagA-positive Helicobacter pylori is a risk factor for the development of severe gastritis and gastric cancer (GC). CagA protein is injected into gastric epithelial cells and deregulates a variety of cellular signaling molecules. Phospholipase D (PLD) is elevated in many different types of human cancers and has been implicated as a critical factor in inflammation and carcinogenesis. In this study, we show that infection with cagA-positive H. pylori in GC cells significantly induces PLD1 expression via CagA-dependent activation of nuclear factor κB (NFκB). Interestingly, the level of PLD1 protein and IκBα phosphorylation is aberrantly upregulated in H. pylori-infected human GC tissues. Infection with cagA-positive H. pylori and expression of CagA enhanced the binding of NFκB to the PLD1 promoter, and two functional NFκB-binding sites were identified within the PLD1 promoter. Rebamipide, a mucosal-protective antiulcer agent, abolished H. pylori cagA-induced PLD1 expression via inhibition of binding of NFκB to the PLD1 promoter, and also inhibited PLD activity. Moreover, rebamipide suppressed H. pylori-induced matrix metalloproteinase-9, interleukin-8 and activation-induced cytidine deaminase expression as well as invasion of GC cells through downregulation of PLD1. Our data suggest that H. pylori cagA targets PLD1 for invasion of GC cells, and rebamipide might contribute to the antitumorigenic effect of GC cells via inhibition of the H. pylori cagA-NFκB-PLD1 signaling pathway.
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, Republic of Korea.
D W
DW
Kang
W C
WC
Hwang
M H
MH
Park
G-H
GH
Ko
W-S
WS
Ha
K-S
KS
Kim
Y-C
YC
Lee
K-Y
KY
Choi
D S
DS
Min
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000502:physiology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D016480:Helicobacter pylori / Q000187:drug effects*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D010739:Phospholipase D / Q000235:genetics* / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects
D000897:Anti-Ulcer Agents; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016328:NF-kappa B; D015363:Quinolones; C080866:cagA protein, Helicobacter pylori; D010739:Phospholipase D; C106801:phospholipase D1; C052785:rebamipide; D000409:Alanine