Open Access

Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor

  • Authors:
    • Koji Izumi
    • Yichun Zheng
    • Yi Li
    • Jacqueline Zaengle
    • Hiroshi Miyamoto
  • View Affiliations

  • Published online on: August 21, 2012     https://doi.org/10.3892/ijo.2012.1593
  • Pages: 1587-1592
  • Copyright: © Izumi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Androgen receptor (AR) signals have been suggested to contribute to bladder tumorigenesis and cancer progression. Activation of epidermal growth factor receptor (EGFR) also leads to stimulation of bladder tumor growth. However, crosstalk between AR and EGFR pathways in bladder cancer remains uncharacterized. We have recently shown that androgens activate the EGFR pathway in bladder cancer cells. The purpose of this study was to investigate the effects of EGF on AR activity in bladder cancer. EGF increased AR transcriptional activity by 1.2-, 1.9- and 2.0-fold in UMUC3, 5637-AR and J82-AR cell lines, respectively, over mock treatment and a specific EGFR inhibitor, PD168393, antagonized the EGF effect. Combined treatment of EGF and dihydrotestosterone (DHT) further induced AR transactivation while an AR antagonist, hydroxyflutamide (HF), abolished the effect of not only DHT but also EGF. In growth assays, EGF alone/DHT alone/EGF+DHT increased cell numbers by 16/12/19%, 6/14/18% and 30/12/38% in UMUC3-control-shRNA, 5637-AR and J82-AR, respectively, whereas the effects of EGF were marginal or less significant in UMUC3-AR-shRNA (8%) or AR-negative 5637-V (<1%) and J82-V (17%) cells. HF treatment at least partially counteracted the EGF effect on the growth of AR-positive cells. Western blotting demonstrated that EGF, especially in the presence of DHT, upregulated the expression of the p160 coactivator TIF2 and HF again blocked this stimulation. Co-immunoprecipitation revealed the association between AR and estrogen receptor (ER)-β or Src in UMUC3 cells and stronger associations with EGF treatment, implying the involvement of the AR/ER/Src complex in EGF-increased AR transactivation and cell growth. Current results, thus, suggest that EGF promotes bladder cancer cell proliferation via modulation of AR signals. Taken together with our previous findings, crosstalk between EGFR and AR pathways can play an important role in the progression of bladder cancer.
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November 2012
Volume 41 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Izumi K, Zheng Y, Li Y, Zaengle J and Miyamoto H: Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor. Int J Oncol 41: 1587-1592, 2012
APA
Izumi, K., Zheng, Y., Li, Y., Zaengle, J., & Miyamoto, H. (2012). Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor. International Journal of Oncology, 41, 1587-1592. https://doi.org/10.3892/ijo.2012.1593
MLA
Izumi, K., Zheng, Y., Li, Y., Zaengle, J., Miyamoto, H."Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor". International Journal of Oncology 41.5 (2012): 1587-1592.
Chicago
Izumi, K., Zheng, Y., Li, Y., Zaengle, J., Miyamoto, H."Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor". International Journal of Oncology 41, no. 5 (2012): 1587-1592. https://doi.org/10.3892/ijo.2012.1593