Browse > Article
http://dx.doi.org/10.1016/j.jgr.2014.06.005

Korean Red Ginseng inhibits apoptosis in neuroblastoma cells via estrogen receptor ${\beta}$-mediated phosphatidylinositol-3 kinase/Akt signaling  

Nguyen, Cuong Thach (School of Pharmacy, Sungkyunkwan University)
Luong, Truc Thanh (School of Pharmacy, Sungkyunkwan University)
Kim, Gyu-Lee (School of Pharmacy, Sungkyunkwan University)
Pyo, Suhkneung (School of Pharmacy, Sungkyunkwan University)
Rhee, Dong-Kwon (School of Pharmacy, Sungkyunkwan University)
Publication Information
Journal of Ginseng Research / v.39, no.1, 2015 , pp. 69-75 More about this Journal
Abstract
Background: Ginseng has been shown to exert antistress effects both in vitro and in vivo. However, the effects of ginseng on stress in brain cells are not well understood. This study investigated how Korean Red Ginseng (KRG) controls hydrogen peroxide-induced apoptosis via regulation of phosphatidylinositol-3 kinase (PI3K)/Akt and estrogen receptor (ER)-${\beta}$ signaling. Methods: Human neuroblastoma SK-N-SH cells were pretreated with KRG and subsequently exposed to $H_2O_2$. The ability of KRG to inhibit oxidative stress-induced apoptosis was assessed in MTT cytotoxicity assays. Apoptotic protein expression was examined byWestern blot analysis. The roles of ER-${\beta}$, PI3K, and p-Akt signaling in KRG regulation of apoptosis were studied using small interfering RNAs and/or target antagonists. Results: Pretreating SK-N-SH cells with KRG decreased expression of the proapoptotic proteins p-p53 and caspase-3, but increased expression of the antiapoptotic protein BCL2. KRG pretreatment was also associated with increased ER-${\beta}$, PI3K, and p-Akt expression. Conversely, ER-${\beta}$ inhibition with small interfering RNA or inhibitor treatment increased p-p53 and caspase-3 levels, but decreased BCL2, PI3K, and p-Akt expression. Moreover, inhibition of PI3K/Akt signaling diminished p-p53 and caspase-3 levels, but increased BCL2 expression. Conclusion: Collectively, the data indicate that KRG represses oxidative stress-induced apoptosis by enhancing PI3K/Akt signaling via upregulation of ER-${\beta}$ expression.
Keywords
apoptosis; estrogen receptor-${\beta}$; oxidative stress; Panax ginseng; phosphatidylinositol-3 kinase/Akt signaling;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Shim MK, Lee YJ. Estrogen receptor is activated by Korean red ginseng in vitro but not in vivo. J Ginseng Res 2012;36:169-75.   DOI
2 Helguero LA, Faulds MH, Gustafsson JA, Haldosen LA. Estrogen receptors alfa (ERalpha) and beta (ERbeta) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11. Oncogene 2005;24: 6605-16.   DOI
3 Madrigal J, Garcia-Bueno B, Caso J, Perez-Nievas B, Leza J. Stress-induced oxidative changes in brain. CNS Neurol Disord Drug Targets 2006;5:561-8.   DOI
4 Cho J, Park W, Lee S, Ahn W, Lee Y. Ginsenoside-Rb1 from Panax ginseng C.A. Meyer activates estrogen receptor-alpha and -beta, independent of ligand binding. J Clin Endocrinol Metab 2004;89:3510-5.   DOI
5 Weiser MJ, Foradori CD, Handa RJ. Estrogen receptor beta in the brain: from form to function. Brain Res Rev 2008;57:309-20.   DOI
6 Zhao C, Dahlman-Wright K, Gustafsson JA. Estrogen signaling via estrogen receptor ${\beta}$. J Biol Chem 2010;285:39575-9.   DOI
7 Chaudhary SC, Singh T, Talwelkar SS, Srivastava RK, Arumugam A, Weng Z, Elmets CA, Afaq F, Kopelvich L, Athar M. Erb-041, an estrogen receptor beta agonist inhibits skin photocarcinogenesis in SKH-1 hairless mice by downregulating WNT signaling pathway. Cancer Prev Res (Phila) 2013;7:186-98.
8 McGrath LT, McGleenon BM, Brennan S, McColl D, McILroy S, Passmore AP. Increased oxidative stress in Alzheimer's disease as assessed with 4-hydroxynonenal but not malondialdehyde. Q J Med 2001;94:485-90.   DOI
9 Handa RJ, Ogawa S, Wang JM, Herbison AE. Roles for oestrogen receptor ${\beta}$ in adult brain function. J Neuroendocrinol 2012;24:160-73.   DOI
10 Pettersson K, Gustafsson JA. Role of estrogen receptor beta in estrogen action. Annu Rev Physiol 2001;63:165-92.   DOI
11 Islander U, Erlandsson MC, Hasseus B, Jonsson CA, Ohlsson C, Gustafsson JA, Dahlgren U, Carlsten H. Influence of oestrogen receptor ${\alpha}$ and ${\beta}$ on the immune system in aged female mice. Immunology 2003;110:149-57.   DOI
12 Mannella P, Brinton R. Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. J Neurosci 2006;26: 9439-47.   DOI
13 Lee YR, Park J, Yu HN, Kim JS, Youn HJ, Jung SH. Up-regulation of PI3K/Akt signaling by 17${\beta}$-estradiol through activation of estrogen receptor-${\alpha}$ , but not estrogen receptor-${\beta}$, and stimulates cell growth in breast cancer cells. Biochem Biophys Res Commun 2005;336:1221-6.   DOI
14 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
15 Wang M, Wang Y, Weil B, Abarbanell A, Herrmann J, Tan J, Kelly M, Meldrum DR. Estrogen receptor ${\beta}$ mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia. Am J Physiol Regul Integr Comp Physiol 2009;296:R972-8.   DOI
16 Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez- Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 2004;30: 193-204.   DOI
17 Lee SH, Jung BH, Kim SY, Lee EH, Chung BC. The antistress effect of ginseng total saponin and ginsenoside Rg3 and Rb1 evaluated by brain polyamine level under immobilization stress. Pharmacol Res 2006;54:46-9.   DOI
18 Park SE, Park C, Kim SH, Hossain MA, Kim MY, Chung HY, Son WS, Kim GY, Choi YH, Kim ND. Korean Red Ginseng extract induces apoptosis and decreases telomerase activity in human leukemia cells. J Ethnopharmacol 2009;121:304-12.   DOI
19 Lu JM, Yao Q, Chen C. Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol 2009;7:293-302.   DOI
20 Li QY, Chen L, Fu WH, Li ZD, Wang B, Shi XJ, Zhong MK. Ginsenoside Rb1 inhibits proliferation and inflammatory responses in rat aortic smooth muscle cells. J Agric Food Chem 2011;59:6312-8.   DOI
21 Cheng W, Wu D, Zuo Q, Wang Z, Fan W. Ginsenoside Rb1 prevents interleukin- 1 beta induced inflammation and apoptosis in human articular chondrocytes. Int Orthop 2013;37:2065-70.   DOI
22 Kang J, Rychahou PG, Ishola TA, Mourot JM, Evers BM, Chung DH. N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma. Oncogene 2008;27:3999-4007.   DOI
23 Kim EH, Kim IH, Lee MJ, Thach Nguyen C, Ha JA, Lee SC, Choi S, Choi KT, Pyo S, Rhee DK. Anti-oxidative stress effect of red ginseng in the brain is mediated by peptidyl arginine deiminase type IV (PADI4) repression via estrogen receptor (ER) ${\beta}$ up-regulation. J Ethnopharmacol 2013;148:474-85.   DOI
24 Shin YM, Jung HJ, Choi WY, Lim CJ. Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside Rg3 in cultured mammalian cell lines. Mol Biol Rep 2013;40:269-79.   DOI
25 Li QY, Chen L, Zhu YH, Zhang M, Wang YP, Wang MW. Involvement of estrogen receptor-${\beta}$ in farrerol inhibition of rat thoracic aorta vascular smooth muscle cell proliferation. Acta Pharmacol Sin 2011;32:433-40.   DOI
26 Musser DA, Oseroff AR. The use of tetrazolium salts to determine sites of damage to the mitochondrial electron transport chain in intact cells following in vitro photodynamic therapy with Photofrin II. Photochem Photobiol 1994;59:621-6.
27 Zhang G, Yanamala N, Lathrop KL, Zhang L, Klein-Seetharaman J, Srinivas H. Ligand-independent antiapoptotic function of estrogen receptor-beta in lung cancer cells. Mol Endocrinol 2010;24:1737-47.   DOI
28 Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 2001;21:893-901.   DOI
29 Zhang HM, Rao JN, Guo X, Liu L, Zou T, Turner DJ, Wang JY. Akt kinase activation blocks apoptosis in intestinal epithelial cells by inhibiting caspase-3 after polyamine depletion. J Biol Chem 2004;279:22539-47.   DOI
30 Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, Reusch JE-B. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 2000;275:10761-6.   DOI
31 Choi BH. Oxygen, antioxidants and brain dysfunction. Yonsei Med J 1993;34: 1-10.   DOI
32 Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999;222:236-45.   DOI
33 Herbert V, Shaw S, Jayatilleke E, Stopler-Kasdan T. Most free-radical injury is iron-related: it is promoted by iron, hemin, holoferritin and vitamin C, and inhibited by desferoxamine and apoferritin. Stem Cells 1994;12:289-303.   DOI
34 Basso M, Giraudo S, Corpillo D, Bergamasco B, Lopiano L, Fasano M. Proteome analysis of human substantia nigra in Parkinson's disease. Proteomics 2004;4: 3943-52.   DOI
35 Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME. Regulation of neuronal survival by the serinethreonine protein kinase Akt. Science 1997;275:661-5.   DOI
36 Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231-41.   DOI
37 Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt and apoptosis: size matters. Oncogene 2003;22:8983-98.   DOI
38 Gottlieb T, Leal J, Seger R, Taya Y, Oren M. Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 2002;21:1299-303.   DOI
39 KimY,KimJ,KwonH, Lee D,WonM,KwonY,KimY. KoreanRed Ginseng protects endothelial cells from serum-deprived apoptosis by regulating Bcl-2 family protein dynamics and caspase S-nitrosylation. J Ginseng Res 2013;37:413-24.   DOI
40 Chen S, Liu J, Liu X, Fu Y, Zhang M, Lin Q, Zhu J, Mai L, Shan Z, Yu X, et al. Panax notoginseng saponins inhibit ischemia-induced apoptosis by activating PI3K/ Akt pathway in cardiomyocytes. J Ethnopharmacol 2011;137:263-70.   DOI
41 Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacologica Sinica 2009;30:379-87.   DOI
42 Gamerdinger M, Manthey D, Behl C. Oestrogen receptor subtype-specific repression of calpain expression and calpain enzymatic activity in neuronal cells - implications for neuroprotection against Ca-mediated excitotoxicity. J Neurochem 2006;97:57-68.   DOI
43 Aguirre C, Jayaraman A, Pike C, Baudry M. Progesterone inhibits estrogenmediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-${\beta}$. J Neurochem 2010;115:1277-87.   DOI
44 Kim JH, Cho SY, Lee JH, Jeong SM, Yoon IS, Lee BH, Lee JH, Pyo MK, Lee SM, Chung JM, et al. Neuroprotective effects of ginsenoside Rg3 against homocysteine- induced excitotoxicity in rat hippocampus. Brain Res 2007;1136: 190-9.   DOI