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Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino‐terminal domain

Prostate cancer (PCa) often recurs as incurable castration‐resistant prostate cancer (CRPC) after the failure of androgen deprivation therapy. CRPC development relies on androgen receptor (AR) signaling. The IL6/STAT3 pathway is also a key driver of CRPC. The crosstalk between IL6/STAT3 and the AR p...

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Autores principales: Hua, Yaping, Azeem, Waqas, Shen, Yunheng, Zhang, Shoude, Olsen, Jan R., Øyan, Anne M., Ke, Xisong, Zhang, Weidong, Kalland, Karl‐Henning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218398/
https://www.ncbi.nlm.nih.gov/pubmed/30410767
http://dx.doi.org/10.1002/prp2.437
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author Hua, Yaping
Azeem, Waqas
Shen, Yunheng
Zhang, Shoude
Olsen, Jan R.
Øyan, Anne M.
Ke, Xisong
Zhang, Weidong
Kalland, Karl‐Henning
author_facet Hua, Yaping
Azeem, Waqas
Shen, Yunheng
Zhang, Shoude
Olsen, Jan R.
Øyan, Anne M.
Ke, Xisong
Zhang, Weidong
Kalland, Karl‐Henning
author_sort Hua, Yaping
collection PubMed
description Prostate cancer (PCa) often recurs as incurable castration‐resistant prostate cancer (CRPC) after the failure of androgen deprivation therapy. CRPC development relies on androgen receptor (AR) signaling. The IL6/STAT3 pathway is also a key driver of CRPC. The crosstalk between IL6/STAT3 and the AR pathways provides opportunities to explore next‐generation agents to treat PCa. Through screening of around 600 natural compounds in our newly established prostate tumorigenesis model, potential STAT3 signaling inhibitors were found and additionally examined for effects on AR signaling. The small molecular compound 154 exhibited dual effects on IL6/STAT3 and AR pathways. We show here that compound 154 inhibits AR and STAT3 transcriptional activity, reduces the expression of phosphorylation of STAT3 (Y705) and downregulates the mRNA levels of AR target genes. Compound 154 also inhibits protein expression of AR and AR splice variants (ARv567es and AR‐V7) without altering AR mRNA levels. Compound 154 binds to AR directly, but not to STAT3 and is identified as an antagonist of the AR amino‐terminal domain (NTD) by disrupting protein‐protein interactions between STAT3 and the AR NTD. Moreover, compound 154 does not reduce AR nuclear translocation. Compound 154 possesses the potential to become a leading compound in novel therapies against CRPC.
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spelling pubmed-62183982018-11-08 Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino‐terminal domain Hua, Yaping Azeem, Waqas Shen, Yunheng Zhang, Shoude Olsen, Jan R. Øyan, Anne M. Ke, Xisong Zhang, Weidong Kalland, Karl‐Henning Pharmacol Res Perspect Original Articles Prostate cancer (PCa) often recurs as incurable castration‐resistant prostate cancer (CRPC) after the failure of androgen deprivation therapy. CRPC development relies on androgen receptor (AR) signaling. The IL6/STAT3 pathway is also a key driver of CRPC. The crosstalk between IL6/STAT3 and the AR pathways provides opportunities to explore next‐generation agents to treat PCa. Through screening of around 600 natural compounds in our newly established prostate tumorigenesis model, potential STAT3 signaling inhibitors were found and additionally examined for effects on AR signaling. The small molecular compound 154 exhibited dual effects on IL6/STAT3 and AR pathways. We show here that compound 154 inhibits AR and STAT3 transcriptional activity, reduces the expression of phosphorylation of STAT3 (Y705) and downregulates the mRNA levels of AR target genes. Compound 154 also inhibits protein expression of AR and AR splice variants (ARv567es and AR‐V7) without altering AR mRNA levels. Compound 154 binds to AR directly, but not to STAT3 and is identified as an antagonist of the AR amino‐terminal domain (NTD) by disrupting protein‐protein interactions between STAT3 and the AR NTD. Moreover, compound 154 does not reduce AR nuclear translocation. Compound 154 possesses the potential to become a leading compound in novel therapies against CRPC. John Wiley and Sons Inc. 2018-11-05 /pmc/articles/PMC6218398/ /pubmed/30410767 http://dx.doi.org/10.1002/prp2.437 Text en © 2018 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Hua, Yaping
Azeem, Waqas
Shen, Yunheng
Zhang, Shoude
Olsen, Jan R.
Øyan, Anne M.
Ke, Xisong
Zhang, Weidong
Kalland, Karl‐Henning
Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino‐terminal domain
title Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino‐terminal domain
title_full Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino‐terminal domain
title_fullStr Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino‐terminal domain
title_full_unstemmed Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino‐terminal domain
title_short Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino‐terminal domain
title_sort dual androgen receptor (ar) and stat3 inhibition by a compound targeting the ar amino‐terminal domain
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218398/
https://www.ncbi.nlm.nih.gov/pubmed/30410767
http://dx.doi.org/10.1002/prp2.437
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