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

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 unchara...

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Autores principales: IZUMI, KOJI, ZHENG, YICHUN, LI, YI, ZAENGLE, JACQUELINE, MIYAMOTO, HIROSHI
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583640/
https://www.ncbi.nlm.nih.gov/pubmed/22922989
http://dx.doi.org/10.3892/ijo.2012.1593
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author IZUMI, KOJI
ZHENG, YICHUN
LI, YI
ZAENGLE, JACQUELINE
MIYAMOTO, HIROSHI
author_facet IZUMI, KOJI
ZHENG, YICHUN
LI, YI
ZAENGLE, JACQUELINE
MIYAMOTO, HIROSHI
author_sort IZUMI, KOJI
collection PubMed
description 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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spelling pubmed-35836402013-03-04 Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor IZUMI, KOJI ZHENG, YICHUN LI, YI ZAENGLE, JACQUELINE MIYAMOTO, HIROSHI Int J Oncol Articles 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. D.A. Spandidos 2012-08-21 /pmc/articles/PMC3583640/ /pubmed/22922989 http://dx.doi.org/10.3892/ijo.2012.1593 Text en Copyright © 2012, Spandidos Publications http://creativecommons.org/licenses/by/3.0 This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
spellingShingle Articles
IZUMI, KOJI
ZHENG, YICHUN
LI, YI
ZAENGLE, JACQUELINE
MIYAMOTO, HIROSHI
Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor
title Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor
title_full Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor
title_fullStr Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor
title_full_unstemmed Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor
title_short Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor
title_sort epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583640/
https://www.ncbi.nlm.nih.gov/pubmed/22922989
http://dx.doi.org/10.3892/ijo.2012.1593
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