Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Molecular Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1107-3756 Online ISSN: 1791-244X
Journal Cover
June-2014 Volume 33 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
June-2014 Volume 33 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway

  • Authors:
    • Hai-Rong Ma
    • Jie Wang
    • Yiu-Fai Chen
    • Hua Chen
    • Wei-Shan Wang
    • Haji Akber Aisa
  • View Affiliations / Copyright

    Affiliations: The Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, P.R. China, Key Laboratory of Xinjiang Endemic Phytomedicine Resources, Ministry of Education, College of Pharmacy, Shihezi University, Shihezi 832002, P.R. China, Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA, School of Medicine, Shihezi University, Shihezi 832002, P.R. China, The State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, P.R. China
  • Pages: 1627-1634
    |
    Published online on: April 3, 2014
       https://doi.org/10.3892/ijmm.2014.1722
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Icariin (ICA) and icaritin (ICT), with a similar structure to genistein, are the important bioactive components of the genus Epimedium, and regulate many cellular processes. In the present study, using the estrogen receptor (ER)-negative breast cancer cell line, SKBr3, as a model, we examined the hypothesis that ICA and ICT at low concentrations stimulate SKBr3 cell proliferation in vitro through the functional membrane, G protein‑coupled estrogen receptor 1 (GPER1), mediated by the epithelial growth factor receptor (EGFR)‑mitogen-activated protein kinase (MAPK) signaling pathway. MTT assay revealed that ICA and ICT at doses of 1 nM to 1 µM markedly stimulated SKBr3 cell proliferation in a dose-dependent manner. The ICA- and ICT-stimulated cell growth was completely suppressed by the GPER1 antagonist, G-15, indicating that the ICA‑ and ICT-stimulated cell proliferation was mediated by GPER1 activation. Semi-quantitative RT-PCR analysis revealed that treatment with ICA and ICT enhanced the transcription of c-fos, a proliferation-related early gene. The ICA- and ICT-stimulated mRNA expression was markedly attenuated by G-15, AG-1478 (an EGFR antagonist) or PD98059 (a MAPK inhibitor). Our data also demonstrated that ICA and ICT increased the phosphorylation of ERK1/2. The ICA- and ICT-stimulated ERK1/2 phosphorylation was blocked by pre-treatment of the cells with G-15 and AG-1478 or PD 98059. Flow cytometric analysis confirmed that the ICA- and ICT-stimulated SKBr3 cell proliferation involved the GPER1-mediated modulation of the EGFR‑MAPK signaling pathway. To the best of our knowledge, our current findings demonstrate for the first time that ICA and ICT promote the progression of ER-negative breast cancer through the activation of membrane GPER1.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Owman C, Blay P, Nilsson C and Lolait SJ: Cloning of human cDNA encoding a novel heptahelix receptor expressed in Burkitt’s lymphoma and widely distributed in brain and peripheral tissues. Biochem Bioph Res Co. 228:285–292. 1996.PubMed/NCBI

2 

Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S and Gustafsson JA: Cloning of a novel estrogen receptor expressed in rat prostate and ovary. PNAS. 93:5925–5930. 1996. View Article : Google Scholar : PubMed/NCBI

3 

Carmeci C, Thompson DA, Ring HZ, Francke U and Weigel RJ: Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics. 45:607–617. 1997. View Article : Google Scholar : PubMed/NCBI

4 

Bouskine A, Nebout M, Bruecker-Davis F, Benahmed M and Fenichel P: Low doses of bisphenol A promote human seminoma cell proliferation by activating PKA and PKG via a membrane G-protein-coupled estrogen receptor. Environ Health Persp. 117:1053–1058. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Filardo EJ: Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer. J Steroid Biochem. 80:231–238. 2002. View Article : Google Scholar : PubMed/NCBI

6 

Revankar CM: A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 307:1625–1630. 2005. View Article : Google Scholar : PubMed/NCBI

7 

Pearce ST and Jordan VC: The biological role of estrogen receptors α and β in cancer. Crit Rev Oncol Hematol. 50:3–22. 2004.

8 

Prossnitz ER, Sklar LA, Oprea TI and Arterburn JB: GPR30: a novel therapeutic target in estrogen-related disease. Trends Pharmacol Sci. 29:116–123. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Ma H, He X, Yang Y, Li M, Hao D and Jia Z: The genus Epimedium: An ethnopharmacological and phytochemical review. J Ethnopharmacol. 134:519–541. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Huang X, Zhu D and Lou Y: A novel anticancer agent, icaritin, induced cell growth inhibition, G1 arrest and mitochondrial transmembrane potential drop in human prostate carcinoma PC-3 cells. Eur J Pharmacol. 564:26–36. 2007. View Article : Google Scholar

11 

Chung BH, Kim JD, Kim CK, Kim JH, Won MH, Lee HS, et al: Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells. Biochem Bioph Res Co. 376:404–408. 2008. View Article : Google Scholar : PubMed/NCBI

12 

Zhang L, Zhang X, Li KF, Li DX, Xiao YM, Fan YJ, et al: Icariin promotes extracellular matrix synthesis and gene expression of chondrocytes in vitro. Phytother Res. 26:1385–1392. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Ming LG, Chen KM and Xian CJ: Functions and action mechanisms of flavonoids genistein and icariin in regulating bone remodeling. J Cell Physiol. 228:513–521. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Wang ZQ and Lou YJ: Proliferation-stimulating effects of icaritin and desmethylicaritin in MCF-7 cells. Eur J Pharmacol. 504:147–153. 2004. View Article : Google Scholar : PubMed/NCBI

15 

Yu Y, Yan H, Hu S and Zhang J: Study on the estrogen-like effects of Epimedium extractive. J Xi’an Jiao tong Univ (Med Sci). 30:373–376. 2009.

16 

Guo Y, Zhang X, Meng J and Wang ZY: An anticancer agent icaritin induces sustained activation of the extracellular signal-regulated kinase (ERK) pathway and inhibits growth of breast cancer cells. Eur J Pharmacol. 658:114–122. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Ye HY and Lou YJ: Estrogenic effects of two derivatives of icariin on human breast cancer MCF-7 cells. Phytomedicine. 12:735–741. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Levin ER: Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol Endocrinol. 17:309–317. 2002. View Article : Google Scholar : PubMed/NCBI

19 

Razandi M: Proximal events in signaling by plasma membrane estrogen receptors. J Biol Chem. 278:2701–2712. 2002. View Article : Google Scholar : PubMed/NCBI

20 

Fujiwara S, Terai Y, Kawaguchi H, Takai M, Yoo S, Tanaka Y, et al: GPR30 regulates the EGFR-Akt cascade and predicts lower survival in patients with ovarian cancer. J Ovarian Res. 5:352012. View Article : Google Scholar : PubMed/NCBI

21 

Filardo EJ, Quinn JA, Bland KI and Frackelton AR Jr: 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. 2000. View Article : Google Scholar

22 

Du GQ, Zhou L, Chen XY, Wan XP and He YY: The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells. Biochem Bioph Res Co. 420:343–349. 2012. View Article : Google Scholar : PubMed/NCBI

23 

Albanito L, Madeo A, Lappano R, Vivacqua A, Rago V, Carpino A, et al: G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17 beta-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res. 67:1859–1866. 2007. View Article : Google Scholar : PubMed/NCBI

24 

Vivacqua A, Bonofiglio D, Albanito L, Madeo A, Rago V, Carpino A, et al: 17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the G protein-coupled receptor GPR30. Mol Pharmacol. 70:1414–1423. 2006. View Article : Google Scholar : PubMed/NCBI

25 

Maggiolini M: The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17-estradiol and phytoestrogens in breast cancer cells. J Biol Chem. 279:27008–27016. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Ma H, Lu Z, Sun Y, Peng T, Shuai Z, Ma Y, et al: Selection of donor nuclei in somatic cell-mediated gene transfer using a co-transfection method. J Reprod Develop. 53:95–104. 2007. View Article : Google Scholar : PubMed/NCBI

27 

Kang K, Lee SB, Jung SH, Cha KH, Park WD, Sohn YC, et al: Tectoridin, a poor ligand of estrogen receptor α, exerts its estrogenic effects via an ERK-dependent pathway. Mol Cells. 27:351–357. 2009.PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Ma H, Wang J, Chen Y, Chen H, Wang W and Aisa HA: Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway. Int J Mol Med 33: 1627-1634, 2014.
APA
Ma, H., Wang, J., Chen, Y., Chen, H., Wang, W., & Aisa, H.A. (2014). Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway. International Journal of Molecular Medicine, 33, 1627-1634. https://doi.org/10.3892/ijmm.2014.1722
MLA
Ma, H., Wang, J., Chen, Y., Chen, H., Wang, W., Aisa, H. A."Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway". International Journal of Molecular Medicine 33.6 (2014): 1627-1634.
Chicago
Ma, H., Wang, J., Chen, Y., Chen, H., Wang, W., Aisa, H. A."Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway". International Journal of Molecular Medicine 33, no. 6 (2014): 1627-1634. https://doi.org/10.3892/ijmm.2014.1722
Copy and paste a formatted citation
x
Spandidos Publications style
Ma H, Wang J, Chen Y, Chen H, Wang W and Aisa HA: Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway. Int J Mol Med 33: 1627-1634, 2014.
APA
Ma, H., Wang, J., Chen, Y., Chen, H., Wang, W., & Aisa, H.A. (2014). Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway. International Journal of Molecular Medicine, 33, 1627-1634. https://doi.org/10.3892/ijmm.2014.1722
MLA
Ma, H., Wang, J., Chen, Y., Chen, H., Wang, W., Aisa, H. A."Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway". International Journal of Molecular Medicine 33.6 (2014): 1627-1634.
Chicago
Ma, H., Wang, J., Chen, Y., Chen, H., Wang, W., Aisa, H. A."Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway". International Journal of Molecular Medicine 33, no. 6 (2014): 1627-1634. https://doi.org/10.3892/ijmm.2014.1722
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team