Chemical Research in Chinese Universities

, Volume 29, Issue 5, pp 911–916 | Cite as

Phytoestrogens inhibiting androgen receptor signal and prostate cancer cell proliferation

  • Jing Wu
  • Shu Liu
  • Xiao-yan Shen
  • Nan-yang Yang
  • Ying Liu
  • Ichiro Tsuji
  • Takaki Yamamura
  • Jiang Li
  • Xiao-meng Li
Article

Abstract

The androgen receptor(AR) signaling activated by dihydrotestosterone(DHT) plays critical roles in prostate cancer development and progression. Phytoestrogens, which are diphenolic compounds with estrogen and antiestrogen effects, can bind to estrogen receptors. However, their function on AR signaling has not been fully elucidated. In this study, dual-luciferase reporter assay, immunobloting, docking system test, MTT assay, immunofluorescence and chromatin immunoprecipitation(ChIP) assays were employed to examine the potential effects of three phytoestrogens(genistein, daidzein, flavone) on DHT-activated prostate specific antigen(PSA) activation, cell proliferation and AR transactivation in lymph node carcinoma of prostate(LNCaP) cells. Phytoestrogens were detected to down-regulate DHT-activated AR-mediated PSA promoter transactivation by dual-luciferase reporter system. Furthermore, three phytoestrogens, especially genistein, were demonstrated to significantly decrease AR-activated PSA protein expression by Western blotting analysis. MTT experiment proves that phytoestrogens, especially genistein, remarkably inhibits the DHT-induced cell proliferation in LNCaP cells. To provide reasonable explanations for experimental phenomena mentioned above, we did docking system test and detected phytoestrogens to share the same AR-binding site with DHT. To further prove the competition between phytoestrogen and DHT on AR binding, we examined the effects of phytoestrogens on DHT-activated AR nuclear translocation and immunofluorescence analysis which confirms that phytoestrogens, especially genistein, inhibit DHT-activated androgen receptor nuclear translocation. Results from ChIP show that phytoestrogens down-regulate DHT-induces AR binding to the androgen response elements(AREs, including AREI, AREII, and AREIII) in PSA promoter. Genistein remarkably down-regulates AR, binding to the AREI located in −250— −39 bp and AREIII in −4170— −3978 bp in the presence of DHT. In general, three phytoestrogens were identified to inhibit DHT-AR binding by competitively binding to AR and inhibit AR-mediated transactivation. And genistein shows the strongest effects among three phytoestrogens. Our findings confirm that phytoestrogens are AR antagonist in the regulation of AR-related PSA activation and cell proliferation, which provides valuable insights into the treatment of prostate cancer.

Keywords

Androgen receptor Phytoestrogen Prostate specific antigen(PSA) Prostate cancer 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    Ferlay J., Shin H. R., Bray F., Forman D., Mathers C., Parkin D. M., International Journal of Cancer, 2010, 127(12), 2893CrossRefGoogle Scholar
  2. [2]
    Chang C. S., Kokontis J., Liao S. T., Science, 1988, 240(4850), 324CrossRefGoogle Scholar
  3. [3]
    Heinlein C. A., Chang C., Endocrine Reviews, 2004, 25(2), 276CrossRefGoogle Scholar
  4. [4]
    Rahman M., Miyamoto H., Chang C., Clinical Cancer Research, 2004, 10(7), 2208CrossRefGoogle Scholar
  5. [5]
    Vernon S. E., Williams W. D., The Journal of Urology, 1983, 130(1), 95Google Scholar
  6. [6]
    Reid K. J., Hendy S. C., Saito J., Sorensen P., Nelson C. C., Journal of Biological Chemistry, 2001, 276(4), 2943CrossRefGoogle Scholar
  7. [7]
    Shang Y., Myers M., Brown M., Molecular Cell, 2002, 11, 601CrossRefGoogle Scholar
  8. [8]
    Wu J., Wei W., Yang N. Y., Shen X. Y., Tsuji I., Yamamura T., Li J., Li X. M., Chem. Res. Chinese Universities, 2013, 29(3), 512CrossRefGoogle Scholar
  9. [9]
    Ososki A. L., Kennelly E. J., Phytotherapy Research, 2003, 17(8), 845CrossRefGoogle Scholar
  10. [10]
    Yildiz F., Phytoestrogens in Functional Foods, CRC Press Taylor & Francis Ltd., Boca Raton, 2005, 3CrossRefGoogle Scholar
  11. [11]
    Chuu C. P., Chen R. Y., Kokontis J. M., Hiipakka R. A., Liao S., Cancer Letters, 2009, 275(1), 86CrossRefGoogle Scholar
  12. [12]
    Keri R. A., Ho S. M., Hunt P. A., Knudsen K. E., Soto A. M., Prins G. S., Reproductive Toxicology, 2007, 24(2), 240CrossRefGoogle Scholar
  13. [13]
    Trott O., Olson A. J., Journal of Computational Chemistry, 2010, 31, 455Google Scholar
  14. [14]
    Pereira de Jésus-Tran K., Côté P. L., Cantin L., Blanchet J., Labrie F., Breton R., Protein Science, 2006, 15, 987CrossRefGoogle Scholar
  15. [15]
    Lill M. A., Winiger F., Vedani A., Ernst B., Journal of Medicinal Chemistry, 2005, 48, 5666CrossRefGoogle Scholar
  16. [16]
    Li X. M., Xu Y., Tsuji I., Soybean and Prostate Cancer, InTech Publishiug, Rijeka, 2013, 265Google Scholar
  17. [17]
    Li X. M., Li J., Ichiro T., Naoki N., Yoshikazu N., Zhao X. J., Asian J. Androl., 2008, 10(4), 551CrossRefGoogle Scholar
  18. [18]
    Wang B. F., Wang J. S., Lu J. F., Kao T. H., Chen B. H., Journal of Agricultural and Food Chemistry, 2009, 57(6), 2221CrossRefGoogle Scholar
  19. [19]
    Miodini P., Fioravanti L., di Fronzo G., Cappelletti V., British Journal of Cancer, 1999, 80(8), 1150CrossRefGoogle Scholar
  20. [20]
    Kohen F., Gayer B., Kulik T., Frydman V., Nevo N., Katzburg S., Limor R., Sharon O., Stern N., Somjen D., Journal of Medicinal Chemistry, 2007, 50, 6405CrossRefGoogle Scholar
  21. [21]
    Kousidou O. C., Tzanakakis G. N., Karamanos N. K., Mini Reviews in Medicinal Chemistry, 2006, 6(3), 331CrossRefGoogle Scholar
  22. [22]
    Murata M., Midorikawa K., Koh M., Umezawa K., Kawanishi S., Biochemistry, 2004, 43(9), 2569CrossRefGoogle Scholar
  23. [23]
    Manthey J. A., Guthrie N., Journal of Agricultural and Food Chemistry, 2002, 50(21), 5837CrossRefGoogle Scholar
  24. [24]
    Heemers H. V., Tindall D. J., Endocrine Reviews, 2007, 28(7), 778CrossRefGoogle Scholar
  25. [25]
    Liu G. F., Gao L. Z., Yu Q., Zhang H. M., Wang Z. X., Chem. J. Chinese Universities, 2012, 33(9), 1920Google Scholar
  26. [26]
    Xie J., Zhu J. H., Chem. J. Chinese Universities, 2011, 32(7), 1532Google Scholar
  27. [27]
    Zhou J. R., Gugger E. T., Tanaka T., Guo Y., Blackburn G. L., Clinton S. K., The Journal of Nutrition, 1999, 129(9), 1628Google Scholar
  28. [28]
    Zhang L., Jiao M., Wu D., Wu K., Li X., Zhu G., Yang L., Wang X., Hsieh J. T., He D., Cancer Lett., 2012, 323(1), 48CrossRefGoogle Scholar

Copyright information

© Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH 2013

Authors and Affiliations

  • Jing Wu
    • 1
  • Shu Liu
    • 1
  • Xiao-yan Shen
    • 1
  • Nan-yang Yang
    • 1
  • Ying Liu
    • 2
  • Ichiro Tsuji
    • 3
  • Takaki Yamamura
    • 4
  • Jiang Li
    • 2
  • Xiao-meng Li
    • 1
  1. 1.Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and CytologyNortheast Normal UniversityChangchunP. R. China
  2. 2.Dental HospitalJilin UniversityChangchunP. R. China
  3. 3.Department of Public HealthTohoku UniversitySendaiJapan
  4. 4.Department of Nutritional SciencesMorioka UniversityMoriokaJapan

Personalised recommendations