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Planta Med 2012; 78(2): 115-121
DOI: 10.1055/s-0031-1280346
Biological and Pharmacological Activity
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Astragaloside IV and Cycloastragenol Stimulate the Phosphorylation of Extracellular Signal-Regulated Protein Kinase in Multiple Cell Types

Lisa Y. Yung1 , Wing See Lam1 , Maurice K. C. Ho1 , Yueqing Hu1 , Fanny C. F. Ip1 , Haihong Pang1 , Allison C. Chin2 , Calvin B. Harley2 , Nancy Y. Ip1 , 2 , Yung H. Wong1 , 2
  • 1Biotechnology Research Institute and Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
  • 2TA Therapeutics Limited (a Geron-BRC/HKUST Joint Venture), Hong Kong, China
Further Information

Publication History

received March 18, 2011 revised October 12, 2011

accepted October 16, 2011

Publication Date:
14 November 2011 (online)

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Abstract

Two Chinese herb-derived small molecule telomerase activators, astragaloside IV (AG-IV) and cycloastragenol (CAG), have recently been shown to improve the proliferative response of CD8+ T lymphocytes from HIV-infected patients by upregulating telomerase activity. Here, we examined the signaling mechanism of AG-IV and CAG. Telomerase activity in human embryonic kidney HEK293 fibroblasts was increased upon treatment with increasing concentrations of AG-IV or CAG. Both compounds induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) in a time- and dose-dependent manner in HEK293 cells and HEK-neo keratinocytes. AG-IV and CAG also stimulated ERK phosphorylation in other cell lines of lung, brain, mammary, endothelial, and hematopoietic origins. Use of selective inhibitors and dominant negative mutants revealed the involvement of c-Src, MEK (ERK kinase), and epidermal growth factor receptor in CAG-induced ERK phosphorylation. Our data indicate that AG-IV and CAG may exert their cellular effects through the activation of the Src/MEK/ERK pathway.

Key words

Astragalus membranaceus - Fabaceae - cycloartane triterpenoid saponin - mitogen-activated protein kinase - telomerase activation

Supporting Information

References

  • 1 Bensky D, Gamble A, Kaptchuk T J. Chinese herbal medicine: materia medica. Revised edition. Seattle: Eastland Press; 1993: 581
    Google Scholar
  • 2 Chen G, Huang W. Progress in pharmacological effects of compositions of Astragalus membranaceus.  Chin J New Drugs. 2008;  17 1482-1485
    Google Scholar
  • 3 Ma X Q, Shi Q, Duan J A, Dong T T, Tsim K W. Chemical analysis of Radix Astragali (Huangqi) in China: a comparison with its adulterants and seasonal variations.  J Agric Food Chem. 2002;  50 4861-4866
    Google Scholar
  • 4 Li Z, Cao Q. Effects of astragaloside IV on myocardial calcium transport and cardiac function in ischemic rats.  Acta Pharmacol Sin. 2002;  23 898-904
    Google Scholar
  • 5 Zhang W, Chen H, Zhang C, Liu R, Li H, Chen H. Astragaloside IV from Astragalus membranaceus shows cardioprotection during myocardial ischemia in vivo and in vitro.  Planta Med. 2006;  72 4-8
    Google Scholar
  • 6 Luo Y, Qin Z, Hong Z, Zhang X, Ding D, Fu J, Zhang W, Chen J. Astragaloside IV protects against ischemic brain injury in a murine model of transient focal ischemia.  Neurosci Lett. 2004;  363 218-223
    Google Scholar
  • 7 Yu Q, Zhu T, Zhang Y. Effect of astrgaloside IV on the long-term consequences of renal ischemia-reperfusion injury in rat.  Zhonghua Yi Xue Za Zhi. 2004;  84 1412-1415
    Google Scholar
  • 8 Xu X, Chen X, Ji H, Li P, Bian Y, Yang D, Xu J, Bian Z, Zhang J. Astragaloside IV improved intracellular calcium handling in hypoxia-reoxygenated cardiomyocytes via the sarcoplasmic reticulum Ca-ATPase.  Pharmacology. 2008;  81 325-332
    Google Scholar
  • 9 Zhang W, Hufnagl P, Binder B, Wojta J. Antiinflammatory activity of astragaloside IV is mediated by inhibition of NF-κB activation and adhesion molecule expression.  Thromb Haemost. 2003;  90 904-914
    Google Scholar
  • 10 Zhang Y, Zhu H, Huang C, Cui X, Gao Y, Huang Y, Gong W, Zhao Y, Guo S. Astragaloside IV exerts antiviral effects against coxsackievirus B3 by upregulating interferon-gamma.  J Cardiovasc Pharmacol. 2006;  47 190-195
    Google Scholar
  • 11 Wang Y, Li X, Song C, Hu Z. Effect of astragaloside IV on T, B lymphocyte proliferation and peritoneal macrophage function in mice.  Acta Pharmacol Sin. 2002;  23 263-266
    Google Scholar
  • 12 Xu H, You C, Zhang R, Gao P, Wang Z. Effects of Astragalus polysaccharides and astragalosides on the phagocytosis of Mycobacterium tuberculosis by macrophages.  J Int Med Res. 2007;  35 84-90
    Google Scholar
  • 13 Fauce S R, Jamieson B D, Chin A C, Mitsuyasu R T, Parish S T, Ng H L, Kitchen C M, Yang O O, Harley C B, Effros R B. Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes.  J Immunol. 2008;  181 7400-7406
    Google Scholar
  • 14 Bosc D G, Goueli B S, Janknecht R. HER2/Neu-mediated activation of the ETS transcription factor ER81 and its target gene MMP-1.  Oncogene. 2001;  20 6215-6224
    Google Scholar
  • 15 Breitschopf K, Zeiher A M, Dimmeler S. Pro-atherogenic factors induce telomerase inactivation in endothelial cells through an Akt-dependent mechanism.  FEBS Lett. 2001;  493 21-25
    Google Scholar
  • 16 Maida Y, Kyo S, Kanaya T, Wang Z, Yatabe N, Tanaka M, Nakamura M, Ohmichi M, Gotoh N, Murakami S, Inoue M. Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway.  Oncogene. 2002;  21 4071-4079
    Google Scholar
  • 17 Kam A Y, Liu A M, Wong Y H. Formyl peptide-receptor like-1 requires lipid raft and extracellular signal-regulated protein kinase to activate inhibitor-κB kinase in human U87 astrocytoma cells.  J Neurochem. 2007;  103 1553-1566
    Google Scholar
  • 18 Liu A M, Lo R K, Wong C S, Morris C, Wise H, Wong Y H. Activation of STAT3 by Gαs distinctively requires protein kinase A, JNK, and phosphatidylinositol 3-kinase.  J Biol Chem. 2006;  281 35812-35825
    Google Scholar
  • 19 New D C, Wu K, Kwok A W, Wong Y H. G protein-coupled receptor-induced Akt activity in cellular proliferation and apoptosis.  FEBS J. 2007;  274 6025-6036
    Google Scholar
  • 20 Zakian V A. Structure and function of telomeres.  Annu Rev Genet. 1989;  23 579-604
    Google Scholar
  • 21 Goueli B S, Janknecht R. Upregulation of the catalytic telomerase subunit by the transcription factor ER81 and oncogenic HER2/Neu, Ras, or Raf.  Mol Cell Biol. 2004;  24 25-35
    Google Scholar
  • 22 Wang Z, Kyo S, Takakura M, Tanaka M, Yatabe N, Maida Y, Fujiwara M, Hayakawa J, Ohmichi M, Koike K, Inoue M. Progesterone regulates human telomerase reverse transcriptase gene expression via activation of mitogen-activated protein kinase signaling pathway.  Cancer Res. 2000;  60 5376-5381
    Google Scholar
  • 23 Li H, Pinto A R, Duan W, Li J, Toh B H, Liu J P. Telomerase down-regulation does not mediate PC12 pheochromocytoma cell differentiation induced by NGF, but requires MAP kinase signalling.  J Neurochem. 2005;  95 891-901
    Google Scholar
  • 24 Liu A M, Wong Y H. Activation of nuclear factor κB by somatostatin type 2 receptor in pancreatic acinar AR42J cells involves Gα14 and multiple signaling components: a mechanism requiring protein kinase C, calmodulin-dependent kinase II, ERK, and c-Src.  J Biol Chem. 2005;  280 34617-34625
    Google Scholar
  • 25 Tsu R C, Chan J S, Wong Y H. Regulation of multiple effectors by the cloned δ-opioid receptor: stimulation of phospholipase C and type II adenylyl cyclase.  J Neurochem. 1995;  64 2700-2707
    Google Scholar
  • 26 Zhu J, Lee S, Ho M K, Hu Y, Pang H, Ip F C, Chin A C, Harley C B, Ip N Y, Wong Y H. In vitro intestinal absorption and first-pass intestinal and hepatic metabolism of cycloastragenol, a potent small molecule telomerase activator.  Drug Metab Pharmacokinet. 2010;  25 477-486
    Google Scholar
  • 27 Zhu F, Li W, Yin Y, Li W. Effect of astragalosides on activation of extracellular signal regulated kinase in hippocampal neuron after injury induced by hypoxia/reoxygenation.  Acta Univ Med Anhui. 2009;  44 471-474
    Google Scholar
  • 28 Nguyen T T, Scimeca J C, Filloux C, Peraldi P, Carpentier J L, Van Obberghen E. Co-regulation of the mitogen-activated protein kinase, extracellular signal-regulated kinase 1, and the 90-kDa ribosomal S6 kinase in PC12 cells. Distinct effects of the neurotrophic factor, nerve growth factor, and the mitogenic factor, epidermal growth factor.  J Biol Chem. 1993;  268 9803-9810
    Google Scholar
  • 29 Lowes V L, Ip N Y, Wong Y H. Integration of signals from receptor tyrosine kinases and G protein-coupled receptors.  Neurosignals. 2002;  11 5-19
    Google Scholar
  • 30 Traverse S, Seedorf K, Paterson H, Marshall C J, Cohen P, Ullrich A. EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor.  Curr Biol. 1994;  4 694-701
    Google Scholar
  • 31 Ramos J W. The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells.  Int J Biochem Cell Biol. 2008;  40 2707-2719
    Google Scholar
  • 32 Werry T D, Christopoulos A, Sexton P M. Mechanisms of ERK1/2 regulation by seven-transmembrane-domain receptors.  Curr Pharm Des. 2006;  12 1683-1702
    Google Scholar
  • 33 Illario M, Cavallo A L, Bayer K U, Di Matola T, Fenzi G, Rossi G, Vitale M. Calcium/calmodulin-dependent protein kinase II binds to Raf-1 and modulates integrin-stimulated ERK activation.  J Biol Chem. 2003;  278 45101-45108
    Google Scholar
  • 34 Choe E S, Wang J Q. Group I metabotropic glutamate receptors control phosphorylation of CREB, Elk-1 and ERK via a CaMKII-dependent pathway in rat striatum.  Neurosci Lett. 2001;  313 129-132
    Google Scholar
  • 35 Qiu L, Wang Q, Di W, Jiang Q, Schefeller E, Derby S, Wanebo H, Yan B, Wan Y. Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid.  Int J Oncol. 2005;  27 823-830
    Google Scholar
  • 36 Poeckel D, Tausch L, Altmann A, Feisst C, Klinkhardt U, Graff J, Harder S, Werz O. Induction of central signalling pathways and select functional effects in human platelets by beta-boswellic acid.  Br J Pharmacol. 2005;  146 514-524
    Google Scholar
  • 37 Biscardi J S, Maa M C, Tice D A, Cox M E, Leu T H, Parsons S J. c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function.  J Biol Chem. 1999;  274 8335-8343
    Google Scholar
  • 38 Yarden Y. The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities.  Eur J Cancer. 2001;  37 S3-S8
    Google Scholar
  • 39 Xu D, Dwyer J, Li H, Duan W, Liu J P. Ets2 maintains hTERT gene expression and breast cancer cell proliferation by interacting with c-Myc.  J Biol Chem. 2008;  283 23567-23580
    Google Scholar

Prof. Yung Hou Wong

Division of Life Science
The Hong Kong University of Science and Technology

Clear Water Bay, Kowloon

Hong Kong

China

Phone: +85 2 23 58 73 28

Fax: +8 52 23 58 15 52

Email: boyung@ust.hk

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