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Endoplasmic reticulum stress inhibits AR expression via the PERK/eIF2α/ATF4 pathway in luminal androgen receptor triple-negative breast cancer and prostate cancer
Androgen receptor (AR) is an important prognostic marker and therapeutic target in luminal androgen receptor triple-negative breast cancer (LAR TNBC) and prostate cancer (PCa). Endoplasmic reticulum (ER) stress may activate the unfolded protein response (UPR) to regulate associated protein expressio...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748692/ https://www.ncbi.nlm.nih.gov/pubmed/35013318 http://dx.doi.org/10.1038/s41523-021-00370-1 |
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author | Li, Xiaoli Zhou, Duanfang Cai, Yongqing Yu, Xiaoping Zheng, Xiangru Chen, Bo Li, Wenjun Zeng, Hongfang Hassan, Moustapha Zhao, Ying Zhou, Weiying |
author_facet | Li, Xiaoli Zhou, Duanfang Cai, Yongqing Yu, Xiaoping Zheng, Xiangru Chen, Bo Li, Wenjun Zeng, Hongfang Hassan, Moustapha Zhao, Ying Zhou, Weiying |
author_sort | Li, Xiaoli |
collection | PubMed |
description | Androgen receptor (AR) is an important prognostic marker and therapeutic target in luminal androgen receptor triple-negative breast cancer (LAR TNBC) and prostate cancer (PCa). Endoplasmic reticulum (ER) stress may activate the unfolded protein response (UPR) to regulate associated protein expression and is closely related to tumor growth and drug resistance. The effect of ER stress on AR expression and signaling remains unclear. Here, we focused on the regulation and underlying mechanism of AR expression induced by ER stress in LAR TNBC and PCa. Western blotting and quantitative RT-PCR results showed that AR expression was markedly decreased under ER stress induced by thapsigargin and brefeldin A, and this effect was dependent on PERK/eIF2α/ATF4 signaling activation. Chromatin immunoprecipitation-PCR and luciferase reporter gene analysis results showed that ATF4 bound to the AR promoter regions to inhibit its activity. Moreover, ATF4 overexpression inhibited tumor proliferation and AR expression both in vitro and in vivo. Collectively, these results demonstrated that ER stress could decrease AR mRNA and protein levels via PERK/eIF2α/ATF4 signaling in LAR TNBC and PCa. Targeting the UPR may be a treatment strategy for AR-dependent TNBC and PCa. |
format | Online Article Text |
id | pubmed-8748692 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87486922022-01-20 Endoplasmic reticulum stress inhibits AR expression via the PERK/eIF2α/ATF4 pathway in luminal androgen receptor triple-negative breast cancer and prostate cancer Li, Xiaoli Zhou, Duanfang Cai, Yongqing Yu, Xiaoping Zheng, Xiangru Chen, Bo Li, Wenjun Zeng, Hongfang Hassan, Moustapha Zhao, Ying Zhou, Weiying NPJ Breast Cancer Article Androgen receptor (AR) is an important prognostic marker and therapeutic target in luminal androgen receptor triple-negative breast cancer (LAR TNBC) and prostate cancer (PCa). Endoplasmic reticulum (ER) stress may activate the unfolded protein response (UPR) to regulate associated protein expression and is closely related to tumor growth and drug resistance. The effect of ER stress on AR expression and signaling remains unclear. Here, we focused on the regulation and underlying mechanism of AR expression induced by ER stress in LAR TNBC and PCa. Western blotting and quantitative RT-PCR results showed that AR expression was markedly decreased under ER stress induced by thapsigargin and brefeldin A, and this effect was dependent on PERK/eIF2α/ATF4 signaling activation. Chromatin immunoprecipitation-PCR and luciferase reporter gene analysis results showed that ATF4 bound to the AR promoter regions to inhibit its activity. Moreover, ATF4 overexpression inhibited tumor proliferation and AR expression both in vitro and in vivo. Collectively, these results demonstrated that ER stress could decrease AR mRNA and protein levels via PERK/eIF2α/ATF4 signaling in LAR TNBC and PCa. Targeting the UPR may be a treatment strategy for AR-dependent TNBC and PCa. Nature Publishing Group UK 2022-01-10 /pmc/articles/PMC8748692/ /pubmed/35013318 http://dx.doi.org/10.1038/s41523-021-00370-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Li, Xiaoli Zhou, Duanfang Cai, Yongqing Yu, Xiaoping Zheng, Xiangru Chen, Bo Li, Wenjun Zeng, Hongfang Hassan, Moustapha Zhao, Ying Zhou, Weiying Endoplasmic reticulum stress inhibits AR expression via the PERK/eIF2α/ATF4 pathway in luminal androgen receptor triple-negative breast cancer and prostate cancer |
title | Endoplasmic reticulum stress inhibits AR expression via the PERK/eIF2α/ATF4 pathway in luminal androgen receptor triple-negative breast cancer and prostate cancer |
title_full | Endoplasmic reticulum stress inhibits AR expression via the PERK/eIF2α/ATF4 pathway in luminal androgen receptor triple-negative breast cancer and prostate cancer |
title_fullStr | Endoplasmic reticulum stress inhibits AR expression via the PERK/eIF2α/ATF4 pathway in luminal androgen receptor triple-negative breast cancer and prostate cancer |
title_full_unstemmed | Endoplasmic reticulum stress inhibits AR expression via the PERK/eIF2α/ATF4 pathway in luminal androgen receptor triple-negative breast cancer and prostate cancer |
title_short | Endoplasmic reticulum stress inhibits AR expression via the PERK/eIF2α/ATF4 pathway in luminal androgen receptor triple-negative breast cancer and prostate cancer |
title_sort | endoplasmic reticulum stress inhibits ar expression via the perk/eif2α/atf4 pathway in luminal androgen receptor triple-negative breast cancer and prostate cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748692/ https://www.ncbi.nlm.nih.gov/pubmed/35013318 http://dx.doi.org/10.1038/s41523-021-00370-1 |
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