Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.

Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.

Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomeno...

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Autores principales: Dominick G A Burton, Maria G Giribaldi, Anisleidys Munoz, Katherine Halvorsen, Asmita Patel, Merce Jorda, Carlos Perez-Stable, Priyamvada Rai
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Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2013
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Acceso en línea:https://doaj.org/article/e8c108d649c24e299fff0ac2f2a92555
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spelling oai:doaj.org-article:e8c108d649c24e299fff0ac2f2a925552021-11-18T07:39:21ZAndrogen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.1932-620310.1371/journal.pone.0068003https://doaj.org/article/e8c108d649c24e299fff0ac2f2a925552013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23840802/?tool=EBIhttps://doaj.org/toc/1932-6203Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS) affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.Dominick G A BurtonMaria G GiribaldiAnisleidys MunozKatherine HalvorsenAsmita PatelMerce JordaCarlos Perez-StablePriyamvada RaiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e68003 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Dominick G A Burton
Maria G Giribaldi
Anisleidys Munoz
Katherine Halvorsen
Asmita Patel
Merce Jorda
Carlos Perez-Stable
Priyamvada Rai
Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.
description Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS) affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.
format article
author Dominick G A Burton
Maria G Giribaldi
Anisleidys Munoz
Katherine Halvorsen
Asmita Patel
Merce Jorda
Carlos Perez-Stable
Priyamvada Rai
author_facet Dominick G A Burton
Maria G Giribaldi
Anisleidys Munoz
Katherine Halvorsen
Asmita Patel
Merce Jorda
Carlos Perez-Stable
Priyamvada Rai
author_sort Dominick G A Burton
title Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.
title_short Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.
title_full Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.
title_fullStr Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.
title_full_unstemmed Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.
title_sort androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/e8c108d649c24e299fff0ac2f2a92555
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