Browse > Article
http://dx.doi.org/10.1016/j.jgr.2018.08.003

Inhibitory effect of Korean Red Ginseng extract on DNA damage response and apoptosis in Helicobacter pylori-infected gastric epithelial cells  

Kang, Hyunju (Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University)
Lim, Joo Weon (Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University)
Kim, Hyeyoung (Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University)
Publication Information
Journal of Ginseng Research / v.44, no.1, 2020 , pp. 79-85 More about this Journal
Abstract
Background: Helicobacter pylori increases reactive oxygen species (ROS) and induces oxidative DNA damage and apoptosis in gastric epithelial cells. DNA damage activates DNA damage response (DDR) which includes ataxia-telangiectasia-mutated (ATM) activation. ATM increases alternative reading frame (ARF) but decreases mouse double minute 2 (Mdm2). Because p53 interacts with Mdm2, H. pylori-induced loss of Mdm2 stabilizes p53 and induces apoptosis. Previous study showed that Korean Red Ginseng extract (KRG) reduces ROS and prevents cell death in H. pylori-infected gastric epithelial cells. Methods: We determined whether KRG inhibits apoptosis by suppressing DDRs and apoptotic indices in H. pylori-infected gastric epithelial AGS cells. The infected cells were treated with or without KRG or an ATM kinase inhibitor KU-55933. ROS levels, apoptotic indices (cell death, DNA fragmentation, Bax/Bcl-2 ratio, caspase-3 activity) and DDRs (activation and levels of ATM, checkpoint kinase 2, Mdm2, ARF, and p53) were determined. Results: H. pylori induced apoptosis by increasing apoptotic indices and ROS levels. H. pylori activated DDRs (increased p-ATM, p-checkpoint kinase 2, ARF, p-p53, and p53, but decreased Mdm2) in gastric epithelial cells. KRG reduced ROS and inhibited increase in apoptotic indices and DDRs in H. pylori-infected gastric epithelial cells. KU-55933 suppressed DDRs and apoptosis in H. pylori-infected gastric epithelial cells, similar to KRG. Conclusion: KRG suppressed ATM-mediated DDRs and apoptosis by reducing ROS in H. pylori-infected gastric epithelial cells. Supplementation with KRG may prevent the oxidative stress-mediated gastric impairment associated with H. pylori infection.
Keywords
Apoptosis; Gastric epithelial cells; Helicobacter pylori; Panax ginseng;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Zhang Y, Xiong Y. Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. Mol Cell 1999;3:579-91.   DOI
2 Weber JD, Taylor LJ, Roussel MF, Sherr CJ, Bar-Sagi D. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1999;1:20-6.   DOI
3 Li Y, Wu D, Chen B, Ingram A, He L, Liu L, Zhu D, Kapoor A, Tang D. ATM activity contributes to the tumor-suppressing functions of p14ARF. Oncogene 2004;23:7355-65.   DOI
4 Pauklin S, Kristjuhan A, Maimets T, Jaks V. ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress. Biochem Biophys Res Commun 2005;334:386-94.   DOI
5 Wu JY, Gardner BH, Murphy CI, Seals JR, Kensil CR, Recchia J, Beltz GA, Newman GW, Newman MJ. Saponin adjuvant enhancement of antigenspecific immune responses to an experimental HIV-1 vaccine. J Immunol 1992;148:1519-25.
6 Sato K, Mochizuki M, Saiki I, Yoo YC, Samukawa K, Azuma I. Inhibition of tumor angiogenesis and metastasis by a saponin of Panax ginseng, ginsenoside-Rb2. Biol Pharm Bull 1994;17:635-9.   DOI
7 Kaneko H, Nakanishi K. Proof of the mysterious efficacy of ginseng: basic and clinical trials: clinical effects of medical ginseng, Korean red ginseng: specifically, its anti-stress action for prevention of disease. J Pharmacol Sci 2004;95:158-62.   DOI
8 Maffei Facino R, Carini M, Aldini G, Berti F, Rossoni G. Panax ginseng administration in the rat prevents myocardial ischemia-reperfusion damage induced by hyperbaric oxygen: evidence for an antioxidant intervention. Planta Med 1999;65:614-9.   DOI
9 Park S, Yeo M, Jin JH, Lee KM, Kim SS, Choi SY, Hahm KB. Inhibitory activities and attenuated expressions of 5-LOX with red ginseng in Helicobacter pyloriinfected gastric epithelial cells. Dig Dis Sci 2007;52:973-82.   DOI
10 Cho SO, Lim JW, Kim H. Red ginseng extract inhibits the expression of MCP-1 and iNOS in Helicobacter pylori-infected gastric epithelial cells by suppressing the activation of NADPH oxidase and Jak2/Stat3. J Ethnopharmacol 2013;150:761-4.   DOI
11 Bae M, Jang S, Lim JW, Kang J, Bak EJ, Cha JH, Kim H. Protective effect of Korean Red Ginseng extract against Helicobacter pylori-induced gastric inflammation in Mongolian gerbils. J Ginseng Res 2014;38:8-15.   DOI
12 Cho SO, Lim JW, Kim H. Diphenyleneiodonium inhibits apoptotic cell death of gastric epithelial cells infected with H. pylori in a Korean isolate. Yonsei Med J 2015;56:1150-4.   DOI
13 Nakagawa K, Taya Y, Tamai K, Yamaizumi M. Requirement of ATM in phosphorylation of the human p53 protein at serine 15 following DNA doublestrand breaks. Mol Cell Biol 1999;19:2828-34.   DOI
14 Honda R, Yasuda H. Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J 1999;18:22-7.   DOI
15 Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 1992;69:1237-45.   DOI
16 Appella E, Anderson CW. Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem 2001;268:2764-72.   DOI
17 Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria JN, Cliby WA, Shieh SY, Taya Y, Prives C, Abraham RT. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev 1999;13:152-7.   DOI
18 Kamijo T, van de Kamp E, Chong MJ, Zindy F, Diehl JA, Sherr CJ, McKinnon PJ. Loss of the ARF tumor suppressor reverses premature replicative arrest but not radiation hypersensitivity arising from disabled atm function. Cancer Res 1999;59:2464-9.
19 Velimezi G, Liontos M, Vougas K, Roumeliotis T, Bartkova J, Sideridou M, Dereli-Oz A, Kocylowski M, Pateras IS, Evangelou K, et al. Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer. Nat Cell Biol 2013;15:967-77.   DOI
20 Sherr CJ. The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol 2001;2:731-7.   DOI
21 Yang Q, Ji M, Guan H, Shi B, Hou P. Shikonin inhibits thyroid cancer cell growth and invasiveness through targeting major signaling pathways. Clin Endocrinol Metab 2013;98:E1909-17.   DOI
22 Elias J. Positive effect of Mdm2 on p53 expression explains excitability of p53 in response to DNA damage. J Theor Biol 2017;418:94-104.   DOI
23 Misiewsicz J. Management of Helicobacter pylori-related disorders. Eur J Gastroenterol Hepatol 2012;9:S17-20.   DOI
24 Brown LM. Helicobacter pylori: epidemiology and routes of transmission. Epidemiol Rev 2000;22:283-97.   DOI
25 Marshall BJ. Helicobacter pylori. Am J Gastroenterol 1994;89:S116-28.
26 Covacci A, Telford JL, Del Giudice G, Parsonnet J, Rappuoli R. Helicobacter pylori virulence and genetic geography. Science 1999;284:1328-33.   DOI
27 Polk DB, Peek Jr RM. Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer 2010;10:403-14.   DOI
28 Cha B, Lim JW, Kim KH, Kim H. 15-Deoxy-delta 12, 14-prostaglandin J2, NADPH oxidase, and RANTES expression in Helicobacter pylori-infected gastric epithelial cells. J Physiol Pharmacol 2011;62:167-74.
29 Jang SH, Lim JW, Morio T, Kim H. Lycopene inhibits Helicobacter pyloriinduced ATM/ATR-dependent DNA damage response in gastric epithelial AGS cells. Free Radic Biol Med 2012;52:607-15.   DOI
30 Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 2003;3:155-68.   DOI
31 Shieh SY, Ahn J, Tamai K, Taya Y, Prives C. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damageinducible sites. Genes Dev 2000;14:289-300.
32 Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995;80:293-9.   DOI
33 Chehab NH, Malikzay A, Appel M, Halazonetis TD. Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev 2000;14:278-88.
34 Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 1998;281:1677-9.   DOI
35 Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 1998;281:1674-7.   DOI
36 Lahiry L, Saha B, Chakraborty J, Bhattacharyya S, Chattopadhyay S, Banerjee S, Choudhuri T, Mandal D, Bhattacharyya A, Sa G, et al. Contribution of p53-mediated Bax transactivation in theaflavin-induced mammary epithelial carcinoma cell apoptosis. Apoptosis 2008;13:771-81.   DOI
37 Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997;387:296-9.   DOI
38 Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature 1997;387:299-303.   DOI
39 Bieging-Rolett KT, Johnson TM, Brady CA, Beaudry VG, Pathak N, Han S, Attardi LD. $P19^{Arf}$ is required for the cellular response to chronic DNA damage. Oncogene 2016;35:4414-21.   DOI
40 Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 1998;92:713-23.   DOI