Androgen receptor drives cellular senescence.
The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time...
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2012-01-01
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doaj-0e4c38a515374fc1a7f4176f534426e12020-11-25T02:40:00ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0173e3105210.1371/journal.pone.0031052Androgen receptor drives cellular senescence.Yelena MirochnikDorina VeliceasaLatanya WilliamsKelly MaxwellAlexander YemelyanovIrina BudunovaOlga V VolpertThe accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.http://europepmc.org/articles/PMC3293868?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yelena Mirochnik Dorina Veliceasa Latanya Williams Kelly Maxwell Alexander Yemelyanov Irina Budunova Olga V Volpert |
spellingShingle |
Yelena Mirochnik Dorina Veliceasa Latanya Williams Kelly Maxwell Alexander Yemelyanov Irina Budunova Olga V Volpert Androgen receptor drives cellular senescence. PLoS ONE |
author_facet |
Yelena Mirochnik Dorina Veliceasa Latanya Williams Kelly Maxwell Alexander Yemelyanov Irina Budunova Olga V Volpert |
author_sort |
Yelena Mirochnik |
title |
Androgen receptor drives cellular senescence. |
title_short |
Androgen receptor drives cellular senescence. |
title_full |
Androgen receptor drives cellular senescence. |
title_fullStr |
Androgen receptor drives cellular senescence. |
title_full_unstemmed |
Androgen receptor drives cellular senescence. |
title_sort |
androgen receptor drives cellular senescence. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor. |
url |
http://europepmc.org/articles/PMC3293868?pdf=render |
work_keys_str_mv |
AT yelenamirochnik androgenreceptordrivescellularsenescence AT dorinaveliceasa androgenreceptordrivescellularsenescence AT latanyawilliams androgenreceptordrivescellularsenescence AT kellymaxwell androgenreceptordrivescellularsenescence AT alexanderyemelyanov androgenreceptordrivescellularsenescence AT irinabudunova androgenreceptordrivescellularsenescence AT olgavvolpert androgenreceptordrivescellularsenescence |
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