Inhibitory Effect of β-Carotene on Helicobacter pylori-Induced TRAF Expression and Hyper-Proliferation in Gastric Epithelial Cells

Abstract

Helicobacter pylori infection causes the hyper-proliferation of gastric epithelial cells that leads to the development of gastric cancer. Overexpression of tumor necrosis factor receptor associated factor (TRAF) is shown in gastric cancer cells. The dietary antioxidant β-carotene has been shown to counter hyper-proliferation in H. pylori-infected gastric epithelial cells. The present study was carried out to examine the β-carotene mechanism of action. We first showed that H. pylori infection decreases cellular IκBα levels while increasing cell viability, NADPH oxidase activity, reactive oxygen species production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and TRAF1 and TRAF2 gene expression, as well as protein-protein interaction in gastric epithelial AGS cells. We then demonstrated that pretreatment of cells with β-carotene significantly attenuates these effects. Our findings support the proposal that β-carotene has anti-cancer activity by reducing NADPH oxidase-mediated production of ROS, NF-κB activation and NF-κB-regulated TRAF1 and TRAF2 gene expression, and hyper-proliferation in AGS cells. We suggest that the consumption of β-carotene-enriched foods could decrease the incidence of H. pylori-associated gastric disorders. from its complex with cytoplasmic IκBα and translocation to the nucleus, a process that is triggered by reactive oxygen species (ROS) and involves ubiquitin-mediated IκBα degradation [17].Previous studies have implicated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and specifically, the reactive oxygen species (ROS) generated by NADPH oxidase, as potential causative factors in H. pylori-induced gastric injury [18][19][20]. It has been shown that gastric epithelial cells infected with H. pylori contain higher levels of NADPH oxidase activity and consequently, higher levels of ROS, leading to the degradation of IκBα and activation of 21].The antioxidant β-carotene-which is responsible for the orange color of many fruits and vegetables, such as carrots and sweet potatoes-inhibits cell growth and also induces apoptosis and cell cycle arrest in various cancers, such as breast cancer and colon cancer [22,23]. β-Carotene is known to reduce ROS levels in H. pylori-infected gastric epithelial cells [5]. Therefore, we hypothesized that β-carotene might inhibit H. pylori-induced up-regulation of TRAF1 and TRAF2 and thereby inhibit NF-κB activation in gastric epithelial cells.

Dietary intake of walnut prevented <i>Helicobacter pylori</i>-associated gastric cancer through rejuvenation of chronic atrophic gastritis

“…Among dietary intervention as non-microbial or dietary approach targeted for H. pylori infection, quite several agents had been studied, including blueberry plants, ( 3 ) phytochemicals from fruits, ( 4 ) genistein from soy rich diet, ( 5 ) dietary antioxidant β-carotene or astaxanthin, ( 6 , 7 ) and n -3 polyunsaturated fatty acids ( n -3 PUFAs)-rich walnut. ( 8 ) Stimulated with significant cancer preventive outcome of walnut that n -PUFAs synthesizing Fat -1 transgenic mice synthesizing n -3 PUFAs such as DHA or EPA significantly resisted from chronic H. pylori -associated gastric carcinogenesis and walnut polyphenol extracts significantly inhibited interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling via peroxisome proliferator-activated receptor γ (PPAR-γ)/suppressors of cytokine secretion (SOCS) 1 stimulation in gastric cells, ( 8 , 9 ) we put hypothesis that dietary intake of walnut ( Juglans regia L.) can reduce H. pylori -associated gastric carcinogenesis.…”

β-Carotene Inhibits Expression of Matrix Metalloproteinase-10 and Invasion in Helicobacter pylori-Infected Gastric Epithelial Cells

“…However, our previous study showed that a low concentration (0.5 and 1 µM) of β-carotene reduced ROS levels and inhibited NF-B activation, NF-B-regulated expression of tumor necrosis factor receptor associated factor (TRAF), and hyper-proliferation in H. pylori -infected gastric epithelial cells [ 49 ]. A low concentration of β-carotene (0.15 and 0.3 µM) inhibited peroxynitrite anion-induced lipid peroxide production in rat brain synaptosomes [ 50 ].…”

Pathways of Gastric Carcinogenesis, Helicobacter pylori Virulence and Interactions with Antioxidant Systems, Vitamin C and Phytochemicals

“…β-carotene was able to block the H. pylori induced degradation of IκBα, thereby retaining NF-κB in the cytoplasm, preventing its nuclear translocation and activation of nuclear transcription targets, including TRAF1 and TRAF2 gene expression. Clinical prevention studies have suggested oral intake of β-carotene may decrease the risk of gastric cancer in H. pylori endemic areas by as much as 48% [ 85 ].…”

“…The effect of CagA induced chronic atrophic gastritis and decreased secretion of vitamin C into the gastric lumen may explain, in part, the variable efficacy of dietary phytochemicals from fruit and vegetables in prevention studies of gastric dysplasia and adenocarcinoma. There have been positive [ 85 , 145 , 146 , 147 ], negative and equivocal results [ 148 , 149 , 150 , 151 , 152 , 153 ], some of which relate to study power and design, H. pylori virulence, endoscopic assessment, baseline histology, heterogeneity, controlling for other risk factors, assessment of plasma vitamin C status, dietary recall and length of follow-up [ 146 , 147 , 148 , 149 ]. For example, a pooled analysis was performed of 810 prospectively collected non-cardia gastric cancer cases and 1160 matched controls from East Asian countries (Korea, Japan, China), with associated H. pylori CagA status, demographic, lifestyle, smoking and dietary data.…”