Ginsenoside Rg1 exerts estrogen-like activities via ligand-independent activation of ERα pathway

Published on Jan 1, 2008in The Journal of Steroid Biochemistry and Molecular Biology3.813
· DOI :10.1016/J.JSBMB.2007.06.005
Wai-Sum Lau3
Estimated H-index: 3
(PolyU: Hong Kong Polytechnic University),
Robbie Yat-Kan Chan11
Estimated H-index: 11
(PolyU: Hong Kong Polytechnic University)
+ 1 AuthorsMan Sau Wong36
Estimated H-index: 36
(PolyU: Hong Kong Polytechnic University)
Sources
Abstract
Abstract Ginsenoside Rg1, an active ingredient commonly found in ginseng root, was previously demonstrated to be a phytoestrogen that exerted estrogen-like activity without direct interaction with estrogen receptors (ERs) in human breast cancer (MCF-7) cells. The present study was designed to determine the molecular mechanism by which Rg1 exerted estrogenic effects. Co-incubation of MCF-7 cells with 1 μM of ER antagonist ICI182780 abolished the inductive effects of Rg1 on pS2 expression as well as ERE-luciferase activity, suggesting that the estrogenic effects of Rg1 were mediated through the endogenous ERs. To evaluate the relative involvement of ERα and ERβ in mediating the actions of Rg1, ER-negative human embryonic kidney (HEK293) cells were co-transfected with the ERE-luciferase reporter construct and either ERα or ERβ construct. The results showed that Rg1 could activate ERE-luciferase activity via the ERα-mediated pathway in a dose-dependent manner (10−14 to 10−6 M); whereas, the activation of ERβ-mediated ERE-luciferase activity by Rg1 only occur at high concentration (10−6 M). Furthermore, the results showed that 1 pM Rg1 could rapidly induce phosphorylation of the AF-1 domain of ERα at serine 118 residue within the first 5 min of incubation, suggesting that Rg1 activates ERα in a ligand-independent manner. Taken together, our results indicate that Rg1 preferentially activates ERα via phosphorylation of AF-1 domain in the absence of receptor binding. This study is the first to provide evidence that ginsenoside Rg1 exerts estrogen-like actions via ligand-independent activation of ERα pathway.
📖 Papers frequently viewed together
230 Citations
51 Citations
185 Citations
References33
Newest
#1Wen Fang Chen (PolyU: Hong Kong Polytechnic University)H-Index: 11
#2Wai-Sum Lau (PolyU: Hong Kong Polytechnic University)H-Index: 3
Last. Man Sau Wong (PolyU: Hong Kong Polytechnic University)H-Index: 36
view all 5 authors...
Ginsenoside Rg1, an active ingredient in ginseng, was previously shown to be a novel class of potent phytoestrogen. The present study aims at investigating the molecular mechanisms involved in mediating its actions in human breast cancer (MCF-7) cells. Rg1 (1 pM) stimulates cell proliferation (P<0.01) and estrogen-responsive pS2 mRNA expression (P<0.05) without alteration of estrogen receptor alpha (ERα) protein or mRNA expression in MCF-7 cells. In addition, 10−14–10−4 M of Rg1 does not demonst...
51 CitationsSource
#1Khaled RadadH-Index: 14
#2Gabriele Gille (TUD: Dresden University of Technology)H-Index: 22
Last. Wolf-Dieter RauschH-Index: 25
view all 5 authors...
Abstract Ginseng, the root of Panax ginseng C.A. Meyer (Araliaceae), is a well known and popular herbal medicine used worldwide. Among more than 30 ginsenosides, the active ingredients of ginseng, ginsenosides Rb1 and Rg1 are regarded as the main compounds responsible for many pharmaceutical actions of ginseng. In our study, primary cultures from embryonic mouse mesencephala were exposed to neurotoxic glutamate concentration and potential protective effects of these two ginsenosides on survival ...
259 CitationsSource
#1Stefan O. Mueller (Merck KGaA)H-Index: 11
#2Stephanie SimonH-Index: 3
Last. Kenneth S. KorachH-Index: 101
view all 5 authors...
Phytoestrogens exert pleiotropic effects on cellular signaling and show some beneficial effects on estrogen-dependent diseases. However, due to activation/inhibition of the estrogen receptors ERa or ERβ, these compounds may induce or inhibit estrogen action and, therefore, have the potential to disrupt estrogen signaling. We performed a comprehensive analysis and potency comparison of phytoestrogens and their human metabolites for ER binding, induction/ suppression of ERa and ERβ transactivation...
651 CitationsSource
#1Jungyoon Cho (Sejong University)H-Index: 6
#2Wankyu Park (Sejong University)H-Index: 2
Last. Young Joo Lee (Sejong University)H-Index: 24
view all 5 authors...
We studied the estrogenic activity of a component of Panax ginseng, ginsenoside-Rb1. The activity of ginsenoside-Rb1 was characterized in a transient transfection system, using estrogen receptor isoforms and estrogen-responsive luciferase plasmids, in COS monkey kidney cells. Ginsenoside-Rb1 activated both α and β estrogen receptors in a dose-dependent manner with maximal activity observed at 100 μm, the highest concentration examined. Activation was inhibited by the estrogen receptor antagonist...
113 CitationsSource
#1Stefania Catalano (University of Calabria)H-Index: 38
#2Loredana MauroH-Index: 28
Last. Sebastiano AndòH-Index: 56
view all 10 authors...
Abstract Leptin is a hormone with multiple biological actions, produced predominantly by adipose tissue. In humans, plasma levels correlate with total body fat, and high concentrations occur in obese women. Among its functions, leptin is able to stimulate normal and tumor cell growth. We demonstrated that leptin induces aromatase activity in MCF-7 cells evidencing its important role in enhancing in situ estradiol production and promoting estrogen-dependent breast cancer progression. Estrogen rec...
297 CitationsSource
#1Wen-Fang Chen (PolyU: Hong Kong Polytechnic University)H-Index: 8
#2Man Sau Wong (PolyU: Hong Kong Polytechnic University)H-Index: 36
Physiological concentration of genistein, a natural isoflavonoid phytoestrogen, stimulates human breast cancer (MCF-7) cells proliferation. In this study, we hypothesize that low concentration of genistein mimics the action of 17β-estradiol in stimulation of MCF-7 cell growth by enhancement of IGF-I signaling pathway. Genistein, at 1 μm, stimulated the growth of MCF-7 cells. Cell cycle analysis showed that 1 μm genistein significantly increased the S phase and decreased the G0G1 phase of MCF-7 c...
106 CitationsSource
#1Xiaosong Chen (Fujian Medical University)H-Index: 4
#2Fang Fang (Fujian Medical University)H-Index: 5
Last. Ying Chen (Fujian Medical University)H-Index: 4
view all 6 authors...
The neuroprotective mechanism of Rg1 was studied in this paper by means of its obvious anti-apoptotic effect on human SHSY5Y cells. SHSY5Y cells were treated with MPP+ (1-methyl-4-phenyl-pyridinium) for 72 hours to induce apoptosis. During the apoptosis, production of reactive oxygen species (ROS), activation of c-Jun N-terminal kinase (JNK) and activation of caspase-3 were observed. The results showed that the signal transduction pathway of MPP+-induced apoptosis might be ROS to JNK, then to ca...
55 CitationsSource
#1Deborah A. Lannigan (UVA: University of Virginia)H-Index: 24
Abstract Estrogen receptor α (ERα) is phosphorylated on multiple amino acid residues. For example, in response to estradiol binding, human ERα is predominately phosphorylated on Ser-118 and to a lesser extent on Ser-104 and Ser-106. In response to activation of the mitogen-activated protein kinase pathway, phosphorylation occurs on Ser-118 and Ser-167. These serine residues are all located within the activation function 1 region of the N-terminal domain of ERα. In contrast, activation of protein...
595 CitationsSource
#1Young Joo Lee (Sejong University)H-Index: 24
#2Young Ran Jin (SNU: Seoul National University)H-Index: 2
Last. Seung Ki Lee (SNU: Seoul National University)H-Index: 32
view all 7 authors...
Ginseng has been recommended to alleviate the menopausal symptoms, which indicates that components of ginseng very likely contain estrogenic activity. We have examined the possibility that a component ofPanax ginseng, ginsenoside-Rb1, acts by binding to estrogen receptor. We have investigated the estrogenic activity of ginsenoside-Rb1, in a transient transfection system using estrogen-responsive luciferase plasmids in MCF-7 cells. Ginsenoside-Rbb1 activated the transcription of the estrogen-resp...
114 CitationsSource
#1Gloria Patricia Cardona-Gómez (CSIC: Spanish National Research Council)H-Index: 24
#2Pablo Mendez (CSIC: Spanish National Research Council)H-Index: 26
Last. Luis M. Garcia-Segura (CSIC: Spanish National Research Council)H-Index: 84
view all 5 authors...
In the brain, as in other tissues, estradiol interacts with growth factors. One of the growth factors that is involved in the neural actions of estradiol is insulin-like growth factor-I (IGF-I). Estradiol and IGF-I cooperate in the central nervous system to regulate neuronal development, neural plasticity, neuroendocrine events and the response of neural tissue to injury. The precise molecular mechanisms involved in these interactions are still not well understood. In the central nervous system ...
140 CitationsSource
Cited By78
Newest
#1Alexander PanossianH-Index: 30
#2Thomas Efferth (University of Mainz)H-Index: 73
Last. Hildebert Wagner (LMU: Ludwig Maximilian University of Munich)H-Index: 55
view all 11 authors...
Adaptogens comprise a category of herbal medicinal and nutritional products promoting adaptability, resilience, and survival of living organisms in stress. The aim of this review was to summarize the growing knowledge about common adaptogenic plants used in various traditional medical systems (TMS) and conventional medicine and to provide a modern rationale for their use in the treatment of stress-induced and aging-related disorders. Adaptogens have pharmacologically pleiotropic effects on the n...
9 CitationsSource
#1Jee Youn Lee (Kyung Hee University)H-Index: 10
#2Hae Young Choi (Kyung Hee University)H-Index: 4
Last. Tae Young Yune (Kyung Hee University)H-Index: 25
view all 5 authors...
Source
#1Wai Yin PangH-Index: 3
#2Xin Lun WangH-Index: 3
Last. Man Sau WongH-Index: 36
view all 6 authors...
Rhizoma Drynaria (RD) has been widely used for healing bone fractures or related diseases in traditional Chinese medicine. The present study was designed to determine if RD flavonoids (RDTF) could cxert estrogen-like protective actions on bone, Young C57/BL6J mice were ovariectomized (OVX) and treated orally with RDTF (0.087. 0.173 0.346 mg/g/day). 17s-estradiol (2 μg/g/day) or its vehicle for 6 weeks. Bone mineral densities (BMD) was measured by periphcral quantitative computed tomography (pQCT...
3 CitationsSource
#1Mei Tian (SHU: Shanghai University)H-Index: 2
#2Lin-Nan Li (SHU: Shanghai University)H-Index: 1
Last. Zhengtao Wang (SHU: Shanghai University)H-Index: 43
view all 5 authors...
Abstract Traditional Chinese medicine (TCM) has been paid much attentions due to the prevention and treatment of steroid hormone disorders. Ginseng, the root of Panax ginseng C. A. Meyer (Araliaceae), is one of the most valuable herbs in complementary and alternative medicines around the world. A series of dammarane triterpenoid saponins, also known as phytosteroids, were reported as the primary ingredients of Ginseng, and indicated broad spectral pharmacological actions, including anti-cancer, ...
2 CitationsSource
#1Muhammad Irfan (KNU: Kyungpook National University)H-Index: 6
#2Yi-Seong KwakH-Index: 14
Last. Man Hee Rhee (KNU: Kyungpook National University)H-Index: 39
view all 5 authors...
Abstract Cardiovascular diseases are a rapidly growing epidemic with high morbidity and mortality. There is an urgent need to develop nutraceutical-based therapy with minimum side effects to reduce cardiovascular risk. Panax ginseng occupies a prominent status in herbal medicine for its various therapeutic effects against inflammation, allergy, diabetes, cardiovascular diseases, and even cancer, with positive, beneficial, and restorative effects. The active components found in most P. ginseng va...
6 CitationsSource
#1Quan Gui Gao (PolyU: Hong Kong Polytechnic University)H-Index: 6
#2Liping Zhou (PolyU: Hong Kong Polytechnic University)H-Index: 5
Last. Man Sau Wong (PolyU: Hong Kong Polytechnic University)H-Index: 36
view all 6 authors...
Abstract Background Ginsenoside Rg1 was shown to exert ligand-independent activation of estrogen receptor (ER) via mitogen-activated protein kinase–mediated pathway. Our study aimed to delineate the mechanisms by which Rg1 activates the rapid ER signaling pathways. Methods ER-positive human breast cancer MCF-7 cells and ER-negative human embryonic kidney HEK293 cells were treated with Rg1 (10−12M, 10−8M), 17s-estradiol (10−8M), or vehicle. Immunoprecipitation was conducted to investigate the int...
1 CitationsSource
#1Ke-Ke Li (MUC: Minzu University of China)H-Index: 1
#2Xiao-Mei Yan (Dalian Medical University)H-Index: 1
Last. Xiao-Jie Gong (MUC: Minzu University of China)H-Index: 1
view all 5 authors...
Abstract Ginsenoside M1 (M1) was considered to be the main antitumor component of ginsenoside metabolites in the body. In order to enhance its potency on antitumor effect, three novel M1 3′–ester derivatives ( 1c , 2c , 3c ) were synthesized and evaluated. The yield of these derivatives was between 41% and 69%. Compared with M1, 2c and 3c can improve the efficacy of the inhibition on breast cancer MCF–7 and MDA–MB–231 cells, especially for MCF–7 (fold: 0.7–4.2, p 2c and 3c may cause cell autopha...
3 CitationsSource
#1Wanglong Zheng (YZU: Yangzhou University)H-Index: 7
#2Bingjie Wang (YZU: Yangzhou University)H-Index: 4
Last. Zongping LiuH-Index: 25
view all 11 authors...
Zearalenone (ZEA), one of the mycotoxins, exerts different mechanisms of toxicity in different cell types at different doses. It can not only stimulate cell proliferation but also inhibit cell viability, induce cell apoptosis, and cause cell death. Thus, the objective of this review is to summarize the available mechanisms and current evidence of what is known about the cell proliferation or cell death induced by ZEA. An increasing number of studies have suggested that ZEA promoted cell prolifer...
25 CitationsSource
Abstract Terpenes are made of the isoprene unit (C 5 ), and along with their derivatives, terpenoids, they are widely distributed in plants as active ingredients involved in anti-inflammation, anti-carcinogenesis and neuroprotection. Estrogenic terpenes and terpenoids are an important category of phytoestrogens and have been used as traditional medicines. The comprehensive list of estrogenic terpenes and terpenoids includes hemi-, mono-, sesqui-, di-, tri-, tetra- and polyterpenes, their derivat...
19 CitationsSource
Adaptogens are stress-response modifiers that increase an organism's nonspecific resistance to stress by increasing its ability to adapt and survive. The classical reductionist model is insufficiently complex to explain the mechanistic aspects of the physiological notion of “adaptability” and the adaptogenic activity of adaptogens. Here, I demonstrate that (1) the mechanisms of action of adaptogens are impossible to rationally describe using the reductionist concept of pharmacology, whereas the ...
41 CitationsSource