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Divergent androgen regulation of unfolded protein response pathways drives prostate cancer

The unfolded protein response (UPR) is a homeostatic mechanism to maintain endoplasmic reticulum (ER) function. The UPR is activated by various physiological conditions as well as in disease states, such as cancer. As androgens regulate secretion and development of the normal prostate and drive pros...

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Autores principales: Sheng, Xia, Arnoldussen, Yke Jildouw, Storm, Margrethe, Tesikova, Martina, Nenseth, Hatice Zeynep, Zhao, Sen, Fazli, Ladan, Rennie, Paul, Risberg, Bjørn, Wæhre, Håkon, Danielsen, Håvard, Mills, Ian G, Jin, Yang, Hotamisligil, Gökhan, Saatcioglu, Fahri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459818/
https://www.ncbi.nlm.nih.gov/pubmed/25864123
http://dx.doi.org/10.15252/emmm.201404509
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author Sheng, Xia
Arnoldussen, Yke Jildouw
Storm, Margrethe
Tesikova, Martina
Nenseth, Hatice Zeynep
Zhao, Sen
Fazli, Ladan
Rennie, Paul
Risberg, Bjørn
Wæhre, Håkon
Danielsen, Håvard
Mills, Ian G
Jin, Yang
Hotamisligil, Gökhan
Saatcioglu, Fahri
author_facet Sheng, Xia
Arnoldussen, Yke Jildouw
Storm, Margrethe
Tesikova, Martina
Nenseth, Hatice Zeynep
Zhao, Sen
Fazli, Ladan
Rennie, Paul
Risberg, Bjørn
Wæhre, Håkon
Danielsen, Håvard
Mills, Ian G
Jin, Yang
Hotamisligil, Gökhan
Saatcioglu, Fahri
author_sort Sheng, Xia
collection PubMed
description The unfolded protein response (UPR) is a homeostatic mechanism to maintain endoplasmic reticulum (ER) function. The UPR is activated by various physiological conditions as well as in disease states, such as cancer. As androgens regulate secretion and development of the normal prostate and drive prostate cancer (PCa) growth, they may affect UPR pathways. Here, we show that the canonical UPR pathways are directly and divergently regulated by androgens in PCa cells, through the androgen receptor (AR), which is critical for PCa survival. AR bound to gene regulatory sites and activated the IRE1α branch, but simultaneously inhibited PERK signaling. Inhibition of the IRE1α arm profoundly reduced PCa cell growth in vitro as well as tumor formation in preclinical models of PCa in vivo. Consistently, AR and UPR gene expression were correlated in human PCa, and spliced XBP-1 expression was significantly upregulated in cancer compared with normal prostate. These data establish a genetic switch orchestrated by AR that divergently regulates the UPR pathways and suggest that targeting IRE1α signaling may have therapeutic utility in PCa.
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spelling pubmed-44598182015-06-12 Divergent androgen regulation of unfolded protein response pathways drives prostate cancer Sheng, Xia Arnoldussen, Yke Jildouw Storm, Margrethe Tesikova, Martina Nenseth, Hatice Zeynep Zhao, Sen Fazli, Ladan Rennie, Paul Risberg, Bjørn Wæhre, Håkon Danielsen, Håvard Mills, Ian G Jin, Yang Hotamisligil, Gökhan Saatcioglu, Fahri EMBO Mol Med Research Articles The unfolded protein response (UPR) is a homeostatic mechanism to maintain endoplasmic reticulum (ER) function. The UPR is activated by various physiological conditions as well as in disease states, such as cancer. As androgens regulate secretion and development of the normal prostate and drive prostate cancer (PCa) growth, they may affect UPR pathways. Here, we show that the canonical UPR pathways are directly and divergently regulated by androgens in PCa cells, through the androgen receptor (AR), which is critical for PCa survival. AR bound to gene regulatory sites and activated the IRE1α branch, but simultaneously inhibited PERK signaling. Inhibition of the IRE1α arm profoundly reduced PCa cell growth in vitro as well as tumor formation in preclinical models of PCa in vivo. Consistently, AR and UPR gene expression were correlated in human PCa, and spliced XBP-1 expression was significantly upregulated in cancer compared with normal prostate. These data establish a genetic switch orchestrated by AR that divergently regulates the UPR pathways and suggest that targeting IRE1α signaling may have therapeutic utility in PCa. BlackWell Publishing Ltd 2015-06 2015-04-11 /pmc/articles/PMC4459818/ /pubmed/25864123 http://dx.doi.org/10.15252/emmm.201404509 Text en © 2015 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Sheng, Xia
Arnoldussen, Yke Jildouw
Storm, Margrethe
Tesikova, Martina
Nenseth, Hatice Zeynep
Zhao, Sen
Fazli, Ladan
Rennie, Paul
Risberg, Bjørn
Wæhre, Håkon
Danielsen, Håvard
Mills, Ian G
Jin, Yang
Hotamisligil, Gökhan
Saatcioglu, Fahri
Divergent androgen regulation of unfolded protein response pathways drives prostate cancer
title Divergent androgen regulation of unfolded protein response pathways drives prostate cancer
title_full Divergent androgen regulation of unfolded protein response pathways drives prostate cancer
title_fullStr Divergent androgen regulation of unfolded protein response pathways drives prostate cancer
title_full_unstemmed Divergent androgen regulation of unfolded protein response pathways drives prostate cancer
title_short Divergent androgen regulation of unfolded protein response pathways drives prostate cancer
title_sort divergent androgen regulation of unfolded protein response pathways drives prostate cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459818/
https://www.ncbi.nlm.nih.gov/pubmed/25864123
http://dx.doi.org/10.15252/emmm.201404509
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