Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Tectoridin, a Poor Ligand of Estrogen Receptor α, Exerts Its Estrogenic Effects via an ERK-Dependent Pathway

  • Kang, Kyungsu (Natural Products Research Center, Korea Institute of Science and Technology Gangneung Institute) ;
  • Lee, Saet Byoul (Natural Products Research Center, Korea Institute of Science and Technology Gangneung Institute) ;
  • Jung, Sang Hoon (Natural Products Research Center, Korea Institute of Science and Technology Gangneung Institute) ;
  • Cha, Kwang Hyun (Natural Products Research Center, Korea Institute of Science and Technology Gangneung Institute) ;
  • Park, Woo Dong (Division of Marine Molecular Biotechnology, Kangnung National University) ;
  • Sohn, Young Chang (Division of Marine Molecular Biotechnology, Kangnung National University) ;
  • Nho, Chu Won (Natural Products Research Center, Korea Institute of Science and Technology Gangneung Institute)
  • Received : 2008.11.21
  • Accepted : 2008.12.24
  • Published : 2009.03.31
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Abstract

Phytoestrogens are the natural compounds isolated from plants, which are structurally similar to animal estrogen, $17{\beta}$-estradiol. Tectoridin, a major isoflavone isolated from the rhizome of Belamcanda chinensis. Tectoridin is known as a phytoestrogen, however, the molecular mechanisms underlying its estrogenic effect are remained unclear. In this study we investigated the estrogenic signaling triggered by tectoridin as compared to a famous phytoestrogen, genistein in MCF-7 human breast cancer cells. Tectoridin scarcely binds to ER ${\alpha}$ as compared to $17{\beta}$-estradiol and genistein. Despite poor binding to ER ${\alpha}$, tectoridin induced potent estrogenic effects, namely recovery of the population of cells in the S-phase after serum starvation, transactivation of the estrogen response element, and induction of MCF-7 cell proliferation. The tectoridin-induced estrogenic effect was severely abrogated by treatment with U0126, a specific MEK1/2 inhibitor. Tectoridin promoted phosphorylation of ERK1/2, but did not affect phosphorylation of ER ${\alpha}$ at $Ser^{118}$. It also increased cellular accumulation of cAMP, a hallmark of GPR30-mediated estrogen signaling. These data imply that tectoridin exerts its estrogenic effect mainly via the GPR30 and ERK-mediated rapid nongenomic estrogen signaling pathway. This property of tectoridin sets it aside from genistein where it exerts the estrogenic effects via both an ER-dependent genomic pathway and a GPR30-dependent nongenomic pathway.

Keywords

Acknowledgement

Supported by : Korean Research Foundation, Korea Institute of Science and Technology Gangneung Institute intramural

References

  1. Altiok, N., Koyuturk, M., and Altiok, S. (2007). JNK pathway regulates estradiol-induced apoptosis in hormone-dependent human breast cancer cells. Breast Cancer Res. Treat. 105, 247-254 https://doi.org/10.1007/s10549-006-9451-1
  2. Chen, W.F., Huang, M.H., Tzang, C.H., Yang, M., and Wong, M.S. (2003). Inhibitory actions of genistein in human breast cancer (MCF-7) cells. Biochim. Biophys. Acta 1638, 187-196 https://doi.org/10.1016/S0925-4439(03)00082-6
  3. Filardo, E.J., Quinn, J.A., Bland, K.I., and Frackelton, A.R., Jr. (2000). Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol. Endocrinol. 14, 1649-1660 https://doi.org/10.1210/me.14.10.1649
  4. Filardo, E.J., Quinn, J.A., Frackelton, A.R., Jr., and Bland, K.I. (2002). Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Mol. Endocrinol. 16, 70-84 https://doi.org/10.1210/me.16.1.70
  5. Grodstein, F., Chen, J., Pollen, D.A., Albert, M.S., Wilson, R.S., Folstein, M.F., Evans, D.A., and Stampfer, M.J. (2000). Postmenopausal hormone therapy and cognitive function in healthy older women. J. Am. Geriatr. Soc. 48, 746-752 https://doi.org/10.1111/j.1532-5415.2000.tb04748.x
  6. Hsieh, Y.C., Yu, H.P., Frink, M., Suzuki, T., Choudhry, M.A., Schwacha, M.G., and Chaudry, I.H. (2007). G protein-coupled receptor 30-dependent protein kinase A pathway is critical in nongenomic effects of estrogen in attenuating liver injury after trauma-hemorrhage. Am. J. Pathol. 170, 1210-1218 https://doi.org/10.2353/ajpath.2007.060883
  7. Joel, P.B., Traish, A.M., and Lannigan, D.A. (1998). Estradiolinduced phosphorylation of serine 118 in the estrogen receptor is independent of p42/p44 mitogen-activated protein kinase. J. Biol. Chem. 273, 13317-13323 https://doi.org/10.1074/jbc.273.21.13317
  8. Jung, S.H., Lee, Y.S., Lee, S., Lim, S.S., Kim, Y.S., Ohuchi, K., and Shin, K.H. (2003). Anti-angiogenic and anti-tumor activities of isoflavonoids from the rhizomes of Belamcanda chinensis. Planta Med. 69, 617-622 https://doi.org/10.1055/s-2003-41125
  9. Kang, K.A., Lee, K.H., Chae, S., Zhang, R., Jung, M.S., Kim, S.Y., Kim, H.S., Kim, D.H., and Hyun, J.W. (2005). Cytoprotective effect of tectorigenin, a metabolite formed by transformation of tectoridin by intestinal microflora, on oxidative stress induced by hydrogen peroxide. Eur. J. Pharmacol. 519, 16-23 https://doi.org/10.1016/j.ejphar.2005.06.043
  10. Kang, K., Lee, H.J., Kim, C.Y., Lee, S.B., Tunsag, J., Batsuren, D., and Nho, C.W. (2007). The chemopreventive effects of Saussurea salicifolia through induction of apoptosis and phase II detoxification enzyme. Biol. Pharm. Bull. 30, 2352-2359 https://doi.org/10.1248/bpb.30.2352
  11. Kim, Y.P., Yamada, M., Lim, S.S., Lee, S.H., Ryu, N., Shin, K.H., and Ohuchi, K. (1999). Inhibition by tectorigenin and tectoridin of prostaglandin E2 production and cyclooxygenase-2 induction in rat peritoneal macrophages. Biochim. Biophys. Acta 1438, 399-407 https://doi.org/10.1016/S1388-1981(99)00067-0
  12. Lannigan, D.A. (2003). Estrogen receptor phosphorylation. Steroids 68, 1-9 https://doi.org/10.1016/S0039-128X(02)00110-1
  13. Lee, H.W., Choo, M.K., Bae, E.A., and Kim, D.H. (2003). Betaglucuronidase inhibitor tectorigenin isolated from the flower of Pueraria thunbergiana protects carbon tetrachloride-induced liver injury. Liver Int. 23, 221-226 https://doi.org/10.1034/j.1600-0676.2003.00830.x
  14. Lee, H.U., Bae, E.A., and Kim, D.H. (2005). Hepatoprotective effect of tectoridin and tectorigenin on tert-butyl hyperoxide-induced liver injury. J. Pharmacol. Sci. 97, 541-544 https://doi.org/10.1254/jphs.SCZ040467
  15. Maeng, S., Jung, Y., Choi, E., Jeon, J.K., Kim, S., Gen, K., and Sohn, Y.C. (2005). Expression of gonadotropin subunit genes following 4-nonylphenol exposure in masu salmon: effects on transcript levels and promoter activities via estrogen receptor alpha. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 142, 383-390 https://doi.org/10.1016/j.cbpb.2005.08.009
  16. Maggiolini, M., Vivacqua, A., Fasanella, G., Recchia, A.G., Sisci, D., Pezzi, V., Montanaro, D., Musti, A.M., Picard, D., and Ando, S. (2004). The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells. J. Biol. Chem. 279, 27008-27016 https://doi.org/10.1074/jbc.M403588200
  17. Manavathi, B., and Kumar, R. (2006). Steering estrogen signals from the plasma membrane to the nucleus: two sides of the coin. J. Cell. Physiol. 207, 594-604 https://doi.org/10.1002/jcp.20551
  18. Monthakantirat, O., De-Eknamkul, W., Umehara, K., Yoshinaga, Y., Miyase, T., Warashina, T., and Noguchi, H. (2005). Phenolic constituents of the rhizomes of the Thai medicinal plant Belamcanda chinensis with proliferative activity for two breast cancer cell lines. J. Nat. Prod. 68, 361-364 https://doi.org/10.1021/np040175c
  19. Morito, K., Aomori, T., Hirose, T., Kinjo, J., Hasegawa, J., Ogawa, S., Inoue, S., Muramatsu, M., and Masamune, Y. (2002). Interaction of phytoestrogens with estrogen receptors alpha and beta(II). Biol. Pharm. Bull. 25, 48-52 https://doi.org/10.1248/bpb.25.48
  20. Moutsatsou, P. (2007). The spectrum of phytoestrogens in nature: our knowledge is expanding. Hormones (Athens) 6, 173-193
  21. Nakhla, A.M., Khan, M.S., Romas, N.P., and Rosner, W. (1994). Estradiol causes the rapid accumulation of cAMP in human prostate. Proc. Natl. Acad. Sci. USA 91, 5402-5405 https://doi.org/10.1073/pnas.91.12.5402
  22. Prossnitz, E.R., Arterburn, J.B., Smith, H.O., Oprea, T.I., Sklar, L.A., and Hathaway, H.J. (2008). Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annu. Rev. Physiol. 70, 165-190 https://doi.org/10.1146/annurev.physiol.70.113006.100518
  23. Revankar, C.M., Cimino, D.F., Sklar, L.A., Arterburn, J.B., and Prossnitz, E.R. (2005). A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307, 1625-1630 https://doi.org/10.1126/science.1106943
  24. Seidlova-Wuttke, D., Hesse, O., Jarry, H., Rimoldi, G., Thelen, P., Christoffel, V., and Wuttke, W. (2004). Belamcanda chinensis and the thereof purified tectorigenin have selective estrogen receptor modulator activities. Phytomedicine 11, 392-403 https://doi.org/10.1016/j.phymed.2004.01.003
  25. Setchell, K.D., and Cassidy, A. (1999). Dietary isoflavones: biological effects and relevance to human health. J. Nutr. 129, 758S-767S https://doi.org/10.1093/jn/129.3.758S
  26. Shin, K.H., Kim, Y.P., Lim, S.S., Lee, S., Ryu, N., Yamada, M., and Ohuchi, K. (1999). Inhibition of prostaglandin E2 production by the isoflavones tectorigenin and tectoridin isolated from the rhizomes of Belamcanda chinensis. Planta Med. 65, 776-777 https://doi.org/10.1055/s-2006-960868
  27. Simpson, E.R., Misso, M., Hewitt, K.N., Hill, R.A., Boon, W.C., Jones, M.E., Kovacic, A., Zhou, J., and Clyne, C.D. (2005). Estrogen--the good, the bad, and the unexpected. Endocr. Rev. 26, 322-330 https://doi.org/10.1210/er.2004-0020
  28. Thelen, P., Peter, T., Hunermund, A., Kaulfuss, S., Seidlova-Wuttke, D., Wuttke, W., Ringert, R.H., and Seseke, F. (2007). Phytoestrogens from Belamcanda chinensis regulate the expression of steroid receptors and related cofactors in LNCaP prostate cancer cells. BJU Int. 100, 199-203 https://doi.org/10.1111/j.1464-410X.2007.06924.x
  29. Thomas, R.S., Sarwar, N., Phoenix, F., Coombes, R.C., and Ali, S. (2008). Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor-alpha activity. J. Mol. Endocrinol. 40, 173-184 https://doi.org/10.1677/JME-07-0165
  30. Vanparys, C., Maras, M., Lenjou, M., Robbens, J., Van Bockstaele, D., Blust, R., and De Coen, W. (2006). Flow cytometric cell cycle analysis allows for rapid screening of estrogenicity in MCF-7 breast cancer cells. Toxicol. In Vitro 20, 1238-1248 https://doi.org/10.1016/j.tiv.2006.05.002
  31. Weitsman, G.E., Li, L., Skliris, G.P., Davie, J.R., Ung, K., Niu, Y., Curtis-Snell, L., Tomes, L., Watson, P.H., and Murphy, L.C. (2006). Estrogen receptor-alpha phosphorylated at Se$_r118$ is present at the promoters of estrogen-regulated genes and is not altered due to HER-2 overexpression. Cancer Res. 66, 10162-10170 https://doi.org/10.1158/0008-5472.CAN-05-4111

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