title: Lycopene inhibits Helicobacter pylori-induced ATM/ATR-dependent DNA damage response in gastric epithelial AGS cells.
abstract: Oxidative stress linked to DNA damage is involved in the pathogenesis of Helicobacter pylori-associated gastric diseases. The DNA damage response (DDR) coordinates cell-cycle transitions, DNA repair, and apoptosis through the activation of ataxia-telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR) and their target proteins. However, neither H. pylori-induced DDR nor the effects of antioxidants on the DNA damage have been established. This study aimed to investigate the detailed process of H. pylori-induced DNA damage and to examine whether lycopene, a natural antioxidant, inhibits DNA damage and cellular response of gastric epithelial AGS cells infected with H. pylori. AGS cells were cultured with H. pylori in Korean isolates and treated with or without lycopene. Cell viability, DNA damage indices, levels of 8-OH-dG, and reactive oxygen species (ROS) as well as cell-cycle distributions were determined. The activation of ATM, ATR, Chk1, and Chk2; histone H2AX focus formation; activation and induction of p53; and levels of Bax and Bcl-2 and poly(ADP-ribose) polymerase-1 (PARP-1) were assessed. The results showed that H. pylori induced apoptosis in AGS cells with increased Bax and decreased Bcl-2 expression as well as PARP-1 cleavage. Culture with H. pylori led to increases in intracellular ROS, 8-OH-dG, double-strand DNA breaks (DSBs), and DNA fragmentation. H. pylori induced activation of the ATM/Chk2 and ATR/Chk1 pathways, phosphorylation of H2AX and p53, and a delay in the progression of the cells entering the S phase. Lycopene inhibited H. pylori-induced increases in ROS, apoptosis, alterations in cell-cycle distribution, DSBs, and ATM- and ATR-mediated DDR in AGS cells. In conclusion, lycopene may be beneficial for treatment of H. pylori-induced gastric diseases associated with oxidative DNA damage.
authors.affiliation: Department of Food and Nutrition, Brain Korea 21 Project, College of Human Ecology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Jang
authors.affiliation: Department of Food and Nutrition, Brain Korea 21 Project, College of Human Ecology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Joo Weon
authors.initials: JW
authors.lastname: Lim
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo 113-8519, Japan. Electronic address: tmorio.ped@tmd.ac.jp.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Department of Food and Nutrition, Brain Korea 21 Project, College of Human Ecology, Yonsei University, Seoul 120-749, Korea. Electronic address: kim626@yonsei.ac.kr.
authors.forename: Hyeyoung
authors.initials: H
authors.lastname: Kim
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D002338:Carotenoids / Q000494:pharmacology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000473:pathology*; D016481:Helicobacter Infections / Q000378:metabolism* / Q000382:microbiology; D016480:Helicobacter pylori; D006801:Humans; D000077276:Lycopene; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D002338:Carotenoids; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000077276:Lycopene