Skip to main content

Advertisement

SpringerLink
Log in

A novel antiestrogen agent Shikonin inhibits estrogen-dependent gene transcription in human breast cancer cells

  • Brief Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Shikonin (SK) has been isolated and identified as a key bioactive component in an herbal plant, Shikon (gromwell). In this study, we investigated antiestrogen activity of SK in breast cancer cells. In human breast cancer cells, we observed that treatment with SK inhibits tumor cell growth in estrogen receptor α (ERα)-positive, but not ERα-negative breast cancer cells. Estrogen-dependent cell growth was inhibited by co-treatment with SK. A potential molecular mechanism by which SK inhibits estrogen action was explored. We found that SK has no effect on ERα mRNA expression, but decreases its protein level. This effect is associated with an increase in ubiquitinated ERα for degradation. Our results suggest that SK downregulates ERα protein through a proteasome-mediated pathway. We also found that the treatment with SK inhibits estrogen-induced estrogen response elements reporter gene activity. Furthermore, SK inhibits recruitment of ERα at the estrogen-dependent gene promoters, and subsequently suppresses gene expression. Finally, co-treatment with SK enhanced sensitivity of breast cancer cells to endocrine therapy. Collectively, our studies suggested that SK has a potential for antihormone therapy in ERα-positive breast cancer cells, and should serve as a target for new drug developments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Jiangsu Xin Yi Xue Yuan (1986) Dictionary of Chinese Materia Medica. Shanghai Press of Science and Technology, Shanghai

  2. Bown D (1995) Encyclopaedia of herbs and their uses. Dorling Kindersley, London

    Google Scholar 

  3. Lee H, Lin JY (1995) (1988) Antimutagenic activity of extracts from anticancer drugs in Chinese medicine. Mutat Res 204:229–234

    Google Scholar 

  4. Wang GL, Chen CB, Gao JM, Ni H, Wang TS, Chen L (2005) Investigation on the molecular mechanisms of anti-hepatocarcinoma herbs of traditional Chinese medicine by cell cycle microarray. Zhongguo Zhong Yao Za Zhi 30:50–54

    CAS  PubMed  Google Scholar 

  5. Wang W, Li PP (2003) The effects of herb lithospermum extract on MCF-7 cell and estrogen and progestogen levels in mice. Zhongguo Zhong Yao Za Zhi 28:1062–1067

    PubMed  Google Scholar 

  6. Guo XP, Zhang XY, Zhang SD (1991) Clinical trial on the effects of Shikonin mixture on later stage lung cancer. Zhong Xi Yi Jie He Za Zhi 11:598–599

    CAS  PubMed  Google Scholar 

  7. Chen X, Yang L, Oppenheim JJ, Howard MZ (2002) Cellular pharmacology studies of Shikonin derivatives. Phytother Res 16:199–209

    Article  CAS  PubMed  Google Scholar 

  8. Chen X, Yang L, Zhang N, Turpin JA, Buckheit RW, Osterling C, Oppenheim JJ, Howard OM (2003) Shikonin, a component of Chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1. Antimicrob Agents Chemother 47:2810–2816

    Article  CAS  PubMed  Google Scholar 

  9. Yoon Y, Kim YO, Lim NY, Jeon WK, Sung HJ (1999) Shikonin, an ingredient of Lithospermum erythrorhizon induced apoptosis in HL60 human premyelocytic leukemia cell line. Planta Med 65:532–535

    Article  CAS  PubMed  Google Scholar 

  10. Singh F, Gao D, Lebwohl MG, Wei H (2003) Shikonin modulates cell proliferation by inhibiting epidermal growth factor receptor signaling in human epidermoid carcinoma cells. Cancer Lett 200:115–121

    Article  CAS  PubMed  Google Scholar 

  11. Hsu PC, Huang YT, Tsai ML, Wang YJ, Lin JK, Pan MH (2004) Induction of apoptosis by shikonin through coordinative modulation of the Bcl-2 family, p27, and p53, release of cytochrome c, and sequential activation of caspases in human colorectal carcinoma cells. J Agric Food Chem 52:6330–6337

    Article  CAS  PubMed  Google Scholar 

  12. Wu Z, Wu L, Li L, Tashiro S, Onodera S, Ikejima T (2004) p53-mediated cell cycle arrest and apoptosis induced by Shikonin via a caspase-9-dependent mechanism in human malignant melanoma A375-S2 cells. J Pharmacol Sci 94:166–176

    Article  CAS  PubMed  Google Scholar 

  13. Han W, Li L, Qiu S, Lu Q, Pan Q, Gu Y, Luo J, Hu X (2007) Shikonin circumvents cancer drug resistance by induction of a necroptotic death. Mol Cancer Ther 6:1641–1649

    Article  CAS  PubMed  Google Scholar 

  14. Hisa T, Kimura Y, Takada K, Suzuki F, Takigawa M (1998) Shikonin, an ingredient of Lithospermum erythrorhizon, inhibits angiogenesis in vivo and in vitro. Anticancer Res 18:783–790

    CAS  PubMed  Google Scholar 

  15. Yoshimi N, Wang A, Morishita Y, Tanaka T, Sugie S, Kawai K, Yamahara J, Mori H (1992) Modifying effects of fungal and herb metabolites on azoxymethane-induced intestinal carcinogenesis in rats. Jpn J Cancer Res 83:1273–1278

    CAS  PubMed  Google Scholar 

  16. Kapadia GJ, Balasubramanian V, Tokuda H, Konoshima T, Takasaki M, Koyama J, Tagahaya K, Nishino H (1997) Anti-tumor promoting effects of naphthoquinone derivatives on short term Epstein–Barr early antigen activation assay and in mouse skin carcinogenesis. Cancer Lett 113:47–53

    Article  CAS  PubMed  Google Scholar 

  17. Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Engl J Med 354:270–282

    Article  CAS  PubMed  Google Scholar 

  18. Ruff M, Gangloff M, Wurtz JM, Moras D (2000) Estrogen receptor transcription and transactivation: structure–function relationship in DNA- and ligand-binding domains of estrogen receptors. Breast Cancer Res 2:353–359

    Article  CAS  PubMed  Google Scholar 

  19. Jordan VC (2002) The secrets of selective estrogen receptor modulation: cell-specific coregulation. Cancer Cell 1:215–217

    Article  CAS  PubMed  Google Scholar 

  20. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371–1388

    Article  CAS  PubMed  Google Scholar 

  21. Ferguson AT, Lapidus RG, Baylin SB, Davidson NE (1995) Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res 55:2279–2283

    CAS  PubMed  Google Scholar 

  22. Zhou Q, Atadja P, Davidson NE (2007) Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol Ther 6:64–69

    CAS  PubMed  Google Scholar 

  23. Shang Y, Brown M (2002) Molecular determinants for the tissue specificity of SERMs. Science 295:2465–2468

    Article  CAS  PubMed  Google Scholar 

  24. Chen M, Ni J, Chang HC, Lin CY, Muyan M, Yeh S (2009) CCDC62/ERAP75 functions as a coactivator to enhance estrogen receptor beta-mediated transactivation and target gene expression in prostate cancer cells. Carcinogenesis 30:841–850

    Article  CAS  PubMed  Google Scholar 

  25. Zhang Y, Qian RQ, Li PP. Shikonin, an ingredient of Lithospermum erythrorhizon, down-regulates the expression of steroid sulfatase genes in breast cancer cells. Cancer Lett 2009 (Epub ahead of print)

  26. Yang H, Zhou P, Huang H, Chen D, Ma N, Cui QC, Shen S, Dong W, Zhang X, Lian W, Wang X, Dou QP, Liu J (2009) Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo. Int J Cancer 124:2450–2459

    Article  CAS  PubMed  Google Scholar 

  27. Yang F, Chen Y, Duan W, Zhang C, Zhu H, Ding J (2006) SH-7, a new synthesized Shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor. Int J Cancer 119:1184–1193

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Flight Attendants Medical Research Institute (FAMRI YCSA072084 to QZ).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, University of Maryland Stewart Greenebaum Cancer Center, Baltimore, MD, 21201, USA

    Yuan Yao & Qun Zhou

Authors
  1. Yuan Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qun Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qun Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yao, Y., Zhou, Q. A novel antiestrogen agent Shikonin inhibits estrogen-dependent gene transcription in human breast cancer cells. Breast Cancer Res Treat 121, 233–240 (2010). https://doi.org/10.1007/s10549-009-0547-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0547-2

Keywords

Search

Navigation