Abstract
The bacterial pathogen Helicobacter pylori (Hp) is the leading risk factor for the development of gastric cancer. Hp virulence factor, cytotoxin-associated gene A (CagA) interacted with cholesterol-enriched microdomains and leads to induction of inflammation in gastric epithelial cells (AGS). In this study, we identified a triterpenoid methylantcinate B (MAB) from the medicinal mushroom Antrodia camphorata which inhibited the translocation and phosphorylation of CagA and caused a reduction in hummingbird phenotype in HP-infected AGS cells. Additionally, MAB suppressed the Hp-induced inflammatory response by attenuation of NF-κB activation, translocation of p65 NF-κB, and phosphorylation of IκB-α, indicating that MAB modulates CagA-mediated signaling pathway. Additionally, MAB also suppressed the IL-8 luciferase activity and its secretion in HP-infected AGS cells. On the other hand, molecular structure simulations revealed that MAB interacts with CagA similarly to that of cholesterol. Moreover, binding of cholesterol to the immobilized CagA was inhibited by increased levels of MAB. Our results demonstrate that MAB is the first natural triterpenoid which competes with cholesterol bound to CagA leading to attenuation of Hp-induced pathogenesis of epithelial cells. Thus, this study indicates that MAB may have a scope to develop as a therapeutic candidate against Hp CagA-induced inflammation.
Highlights
Chronic infection with the human bacterial pathogen Helicobacter pylori (Hp) causes gastritis and peptic ulceration and increases the carrier’s risk of developing gastric cancer [1]
cytotoxin-associated gene A (CagA) localizes on the inner surface of the plasma membrane and becomes phosphorylated on tyrosine residues by Src family kinases [5]. e translocation and phosphorylation of CagA are triggered by direct interaction of the Hp T4SS with the αα5ββ1 integrin, which is found on the surfaces of epithelial cells [5, 6]. is interaction triggers the delivery of CagA into the host as well as subsequent Src kinase activation. e phosphorylated CagA subsequently
CagA translocation is required in order to exert its effects on host ammation in gastric epithelial cells (AGS) cells, and once within the host cytoplasm CagA can be phosphorylated by tyrosine kinases. erefore, we rst sought to determine if methylantcinate B (MAB) treatment could affect the expression and function of Hp CagA phosphorylation and translocation in AGS cells
Summary
Chronic infection with the human bacterial pathogen Helicobacter pylori (Hp) causes gastritis and peptic ulceration and increases the carrier’s risk of developing gastric cancer [1]. One of the best described effectors molecule is cytotoxin-associated gene A (CagA) which translocated into host gastric epithelial cells by type IV secretion system (T4SS) [2, 3]. Is T4SS represents a needle-like structure ( called T4SS pilus) protruding from the Hp surface and is induced by host cell contact to inject virulence factors including CagA [3]. CagA and the T4SS played a crucial role in gastric cancer development of gerbils [4]. E translocation and phosphorylation of CagA are triggered by direct interaction of the Hp T4SS with the αα5ββ integrin, which is found on the surfaces of epithelial cells [5, 6]. Is interaction triggers the delivery of CagA into the host as well as subsequent Src kinase activation. CagA has been recognized as an oncoprotein that acts in mammals which were demonstrated by a transgenic mouse model [8]
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