Tumor Biology

, Volume 36, Issue 2, pp 967–972 | Cite as

Androgen receptor signaling regulates growth of glioblastoma multiforme in men

  • Xiaoming Yu
  • Yuhua Jiang
  • Wei Wei
  • Ping Cong
  • Yinlu Ding
  • Lei Xiang
  • Kang Wu
Research Article


Although glioblastoma multiforme (GBM) is the most malignant primary human brain cancer with surprisingly high incidence rate in adult men than in women, the exact mechanism underlying this pronounced epidemiology is unclear. Here, we showed significant upregulated androgen receptor (AR) expression in the GBM tissue compared to the periphery normal brain tissue in patients. An expression of AR was further detected in all eight examined human GBM cell lines. To figure out whether AR signaling may play a role in GBM, we used high AR-expressing U87-MG GBM line for further study. We found that activation of transforming growth factor β (TGFβ) receptor signaling by TGFβ1 in GBM significantly inhibited cell growth and increased apoptosis. Moreover, application of active AR ligand 5α-dihydrotestosterone (DHT) significantly decreased the effect of TGFβ1 on GBM growth and apoptosis, suggesting that AR signaling pathway may contradict the effect of TGFβ receptor signaling in GBM. However, neither total protein nor the phosphorylated protein of SMAD3, a major TGFβ receptor signaling downstream effector in GBM, was affected by DHT, suggesting that AR activation may not affect the SMAD3 protein production or phosphorylation of TGFβ receptor and SMAD3. Finally, immunoprecipitation followed by immunoblot confirmed binding of pAR to pSMAD3, which may prevent the DNA binding of pSMAD3 and subsequently prevent its effect on cell growth in GBM. Taken together, our study suggests that AR signaling may promote tumorigenesis of GBM in adult men by inhibiting TGFβ receptor signaling.


Androgen receptor signaling 5α-Dihydrotestosterone Glioblastoma multiforme Transforming growth factor β receptor signaling SMAD3 



This work was supported by independent Innovation Foundation of Shandong University, IIFSDU NO: 2012TS186, Shan Dong provincial Natural Science Foundation (NO: ZR2013HL027) and Shandong traditional Chinese medicine science and technology development program (NO: 2011–212).

Conflicts of interest



  1. 1.
    Schonberg DL, Bao S, Rich JN. Genomics informs glioblastoma biology. Nat Genet. 2013;45:1105–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Li S, Gao Y, Ma W, Guo W, Zhou G, Cheng T, et al. EGFR signaling-dependent inhibition of glioblastoma growth by ginsenoside Rh2. Tumour Biol. 2014;35:5593–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Chen J, Huang Q, Wang F. Inhibition of FoxO1 nuclear exclusion prevents metastasis of glioblastoma. Tumour Biol. 2014;35:7195–200.CrossRefPubMedGoogle Scholar
  4. 4.
    Wang F, Xiao W, Sun J, Han D, Zhu Y. MiRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing akt phosphorylation in glioblastoma. Tumour Biol. 2014.Google Scholar
  5. 5.
    Kabat GC, Etgen AM, Rohan TE. Do steroid hormones play a role in the etiology of glioma? Cancer Epidemiol Biomarkers Prev. 2010;19:2421–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Carroll RS, Zhang J, Dashner K, Sar M, Black PM. Steroid hormone receptors in astrocytic neoplasms. Neurosurgery. 1995;37:496–503. discussion 503–494.CrossRefPubMedGoogle Scholar
  7. 7.
    Hill RA, Wu YW, Kwek P, van den Buuse M. Modulatory effects of sex steroid hormones on brain-derived neurotrophic factor-tyrosine kinase b expression during adolescent development in C57BI/6 mice. J Neuroendocrinol. 2012;24:774–88.CrossRefPubMedGoogle Scholar
  8. 8.
    McEwen BS. Steroid hormones: effect on brain development and function. Horm Res. 1992;37 Suppl 3:1–10.CrossRefPubMedGoogle Scholar
  9. 9.
    Zhu ML, Kyprianou N. Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocr Relat Cancer. 2008;15:841–9.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Massague J. TGFbeta in cancer. Cell. 2008;134:215–30.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A. 2014;111:E1211–1220.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yi JJ, Barnes AP, Hand R, Polleux F, Ehlers MD. TGF-beta signaling specifies axons during brain development. Cell. 2010;142:144–57.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ewen ME, Sluss HK, Whitehouse LL, Livingston DM. TGF beta inhibition of Cdk4 synthesis is linked to cell cycle arrest. Cell. 1993;74:1009–20.CrossRefPubMedGoogle Scholar
  14. 14.
    Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463:676–80.CrossRefPubMedGoogle Scholar
  15. 15.
    Xiao X, Wiersch J, El-Gohary Y, Guo P, Prasadan K, Paredes J, et al. TGFbeta receptor signaling is essential for inflammation-induced but not beta-cell workload-induced beta-cell proliferation. Diabetes. 2013;62:1217–26.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Golestaneh N, Mishra B. TGF-beta, neuronal stem cells and glioblastoma. Oncogene. 2005;24:5722–30.CrossRefPubMedGoogle Scholar
  17. 17.
    Truty MJ, Urrutia R. Basics of TGF-beta and pancreatic cancer. Pancreatology. 2007;7:423–35.CrossRefPubMedGoogle Scholar
  18. 18.
    Buck MB, Knabbe C. TGF-beta signaling in breast cancer. Ann N Y Acad Sci. 2006;1089:119–26.CrossRefPubMedGoogle Scholar
  19. 19.
    Mishra L, Shetty K, Tang Y, Stuart A, Byers SW. The role of TGF-beta and Wnt signaling in gastrointestinal stem cells and cancer. Oncogene. 2005;24:5775–89.CrossRefPubMedGoogle Scholar
  20. 20.
    Akhurst RJ, Derynck R. TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol. 2001;11:S44–51.PubMedGoogle Scholar
  21. 21.
    Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29:117–29.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhu ML, Partin JV, Bruckheimer EM, Strup SE, Kyprianou N. TGF-beta signaling and androgen receptor status determine apoptotic cross-talk in human prostate cancer cells. Prostate. 2008;68:287–95.CrossRefPubMedGoogle Scholar
  23. 23.
    Hayes SA, Zarnegar M, Sharma M, Yang F, Peehl DM, ten Dijke P, et al. SMAD3 represses androgen receptor-mediated transcription. Cancer Res. 2001;61:2112–8.PubMedGoogle Scholar
  24. 24.
    Mei Q, Li F, Quan H, Liu Y, Xu H. Busulfan inhibits growth of human osteosarcoma through miR-200 family micrornas in vitro and in vivo. Cancer Sci. 2014;105:755–62.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Xiaoming Yu
    • 1
  • Yuhua Jiang
    • 1
  • Wei Wei
    • 1
  • Ping Cong
    • 1
  • Yinlu Ding
    • 2
  • Lei Xiang
    • 3
  • Kang Wu
    • 4
  1. 1.Department of Oncologythe Second Hospital of Shandong UniversityJinanChina
  2. 2.Department of General Surgerythe Second Hospital of Shandong UniversityJinanChina
  3. 3.Department of Pathology, School of MedicineShandong UniversityJinanChina
  4. 4.Department of Oncologythe People’s Hospital of LinqingLinqingChina

Personalised recommendations