Molecular & Cellular Toxicology

  • 제2권1호
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  • Pages.15-20
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  • 2006
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  • 1738-642X(pISSN)
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  • 2092-8467(eISSN)
대한독성유전 단백체학회 (The Korean Society of Toxicogenomics and Toxicoproteomics)
권호 표지

Molecular Effects of Genistein on Proliferation and Apoptosis of MCF-7 Cell Line

  • Shin, Hye-Jin (Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology) ;
  • Oh, Young-Jin (Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology) ;
  • Hwang, Seung-Yong (Department of Biochemistry and Molecular Biology, Hanyang University) ;
  • Yoo, Young-Sook (Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology)
  • 발행 : 2006.03.31
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초록

Genistein is a potent, plant-derived isoflavone that displays estrogenic activity at low concentrations but inhibits proliferation at high amounts. However, the molecular mechanism of genistein is not completely understood. In the present study, the biphasic effects (estrogenic and antiestrogenic activity) of genistein on the growth of MCF-7 cells were identified. Genistein within a low range of concentration, $1-10\;{\mu}M$, stimulated proliferation, while $50-100\;{\mu}M$ caused apoptotic cell death. Additionally, genistein at a low concentration induced estrogen receptor (ER)-mediated gene expression and ER phosphorylation. When pre-treated with PD98059, an MEK inhibitor, ER-mediated gene expression and ER phosphorylation by genistein were noticeably increased. However, the increased gene expression and phosphorylation did not enhance cell proliferation. Moreover, it was observed that ER-mediated signaling performs an important role in the MAPK pathway. The proliferation and apoptosis in genistein-treated MCF-7 cells were partially dependent on the Bcl-2 level. The addition of IC1 182, 780, an estrogen receptor antagonist, inhibited Bcl-2 expression induced by genistein. This study suggests that there is a close relationship between Bcl-2 and the ER signaling pathways in MCF-7 cells.

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참고문헌

  1. Adlercreutz, H. Western diet and western diseases: some hormonal and biochemical mechanisms and associations. Scand. J. Clin. Lab. Invest. 50, 3-23 (1990) https://doi.org/10.1080/00365519009085798
  2. Fotsis, T. et al. A dietary-derived inhibitor of in vitro angiogenesis. Proc. Natl. Acad. Sci. 90, 2690-2694 (1993)
  3. Barnes, S. & Peterson, T.G. Biochemical targets of the isoflavone genistein in tumor cell lines. Pro. Soc. Exp. Bio. Med. 208, 103-108 (1995)
  4. Constantinou, A.I. & Huberman, E. Genistein as an inducer of tumor cell differentiation: possible mechanism of action. Pro. Soc. Exp. Bio. Med. 125, 109-115 (1995)
  5. Peterson, G. Evaluation of the biochemical targets of genistein in tumor cell. J. Nutr. 125, 784s-789s (1995)
  6. Matsukawa, Y. et al. Genistein arrests cell cycle progression at G2-M. Cancer Res. 53, 1328-1331 (1993)
  7. Kuzumaki, T., Kobayashi, T. & Ishikawa, K. Genistein induces p21 (Cip1/WAF1) expression and blocks the G1 to S phase transition in mouse fibroblast and melanoma cells. Biochem Biophys Res Commun. 251, 291-295 (1998) https://doi.org/10.1006/bbrc.1998.9462
  8. Koroma, B.M. & de Juan, E Jr. Inhibition of protein tyrosine phosphorylation in endothelial cells: relationship toantiproliferative action of genistein. Biochem. Soc. Trans. 25, 35-40 (1997) https://doi.org/10.1042/bst0250035
  9. Kim, H., Peterson, T.G. & Barnes, S. Mechanisms of action of the soy isoflavone genistein: emerging role for its effects via transforming growth factor beta signaling pathways. Am. J. Clin. Nutr. 68, 1418 -1425 (1998) https://doi.org/10.1093/ajcn/68.6.1418S
  10. Bouker, K.B. & Hilakivi-Clarke, L. Genistein: Does it prevent or promote breast cancer? Environ. Health Perspect. 108, 701-708 (2000) https://doi.org/10.2307/3434722
  11. Markiewicz, L. et al. In vitro bioassays of non-steroidal phytoestrogen. J. Steroid Biochem. Mol. Biol. 45, 399-405 (1993) https://doi.org/10.1016/0960-0760(93)90009-L
  12. Lobenhofer, E.K. & Marks, J.R. Estrogen-induced mitogenesis of MCF-7 cells does not require the induction of mitogen-activated protein kinase activity. J. Steroid Biochem. Mol. Biol. 75, 11-20 (2000) https://doi.org/10.1016/S0960-0760(00)00132-1
  13. Migliaccio, A., Di Domenico, M. & Castoria, G. Tyrosine kinase/p21ras/MAPK pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J. 15, 1292-1300 (1996)
  14. Prifti, S. et al. Synthetic estrogen-mediated activation of JNK intracellular signaling molecule. Gynecol. Endocrinol. 15, 135-141 (2001) https://doi.org/10.1080/713602805
  15. Ahamed, S. et al. Signal transduction through the Ras/Erk pathway is essentialfor the mycoestrogen zearalenone-induced cell-cycle progression in MCF-7 cells. Mol. Carcinog. 30, 88-98 (2001) https://doi.org/10.1002/1098-2744(200102)30:2<88::AID-MC1017>3.0.CO;2-E
  16. Messina, M.J. & Loprinzi, C.L. Soy for Breast Cancer Survivors: A Critical Review of the Literature. J. Nutr. 131, 3095-3108 (2001)
  17. Burow, M.E. et al. Oestrogen-mediated suppression of tumour necrosis factor alpha-induced apoptosis in MCF-7 cells: subversion of Bcl-2 by anti-oestrogens. J. Steroid Biochem. Mol. Biol. 78, 409-418 (2001) https://doi.org/10.1016/S0960-0760(01)00117-0
  18. Harris, M.H. & Thompson, C.B. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ. 7, 1182-1191 (2000) https://doi.org/10.1038/sj.cdd.4400781
  19. Berchem, G.J. et al. Androgens induce resistance to Bcl-2-mediated apoptosis in LNCaP prostate cancer cells. Cancer Res. 554, 735-738 (1995)
  20. Mandal, M. & Kumar, R. Bcl-2 expression regulates sodium butyrate-induced apoptosis in human MCF-7 breast cancer cells. Cell Growth Differ. 73, 311-318 (1996)
  21. Lim, K.B. et al. Induction of apoptosis in mammary gland by a pure anti-estrogen ICI 182,780. Breast Cancer Res. Treat. 68, 127-138 (2001) https://doi.org/10.1023/A:1011929222555
  22. Hsieh, C.Y. et al. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res. 58, 3833-3838 (1998)
  23. Yue, W. et al. Activation of the MAPK pathway enhances sensitivity of MCF-7 breast cancer cells to the mitogenic effect of estradiol. Endocrinology 143, 3221-3229 (2002) https://doi.org/10.1210/en.2002-220186
  24. Jeng, M.H. et al. Role of MAP kinase in the enhanced cell proliferation of long term estrogen deprived human breast cancer cells. Breast Cancer Res. Treat. 62, 167-175 (2000) https://doi.org/10.1023/A:1006406030612
  25. Kinyamu, H.K. & Archer, T.K. Estrogen receptor-dependent proteasomal degradation of the glucocorticoid receptor is coupled to an increase in mdm2 protein expression. Mol Cell Biol. 23, 5867-5881 (2003) https://doi.org/10.1128/MCB.23.16.5867-5881.2003
  26. Bonapace, I.M. et al. 17beta-Estradiol overcomes a G1 block induced by HMG-CoA reductase inhibitors and fosters cell cycle progression without inducing ERK-1 and -2 MAP kinases activation. Oncogene 12, 753-763 (1996)
  27. Li, Y. et al. Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene 18, 3166 -3172 (1999) https://doi.org/10.1038/sj.onc.1202650
  28. Constantinou, A.I., Kamath, N. & Murley, J.S. Genistein inactivates bcl-2, delays the G2/M phase of the cell cycle, and induces apoptosis of human breast adenocarcinoma MCF-7 cells. Eur. J. Cancer 34, 1927-1934 (1998) https://doi.org/10.1016/S0959-8049(98)00198-1
  29. Xu, J. & Loo, G. Different effects of genistein on molecular markers related to apoptosis in two phenotypically dissimilar breast cancer cell lines. J. Cell. Biochem. 82, 78-88 (2001) https://doi.org/10.1002/jcb.1147
  30. Leung, L.K. & Wang, T.T. Bcl-2 is not reduced in the death of MCF-7 cells at low genistein concentration. J. Nutr. 130, 2922-2926 (2000)
  31. Fog, C.K., Christensen, I.J. & Lykkesfeldt, A.E. Characterization of a human breast cancer cell line, MCF-7/ RU58R-1, resistant to the pure antiestrogen RU 58,668. Breast Cancer Res Treat. 91, 133-144 (2005) https://doi.org/10.1007/s10549-004-5871-y