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Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours

Current hormonal therapies for prostate cancer are effective initially, but inevitably tumours progress to an advanced, metastatic stage, often referred to as ‘androgen independent’. However, the androgen receptor (AR) signalling pathway is still key for their growth. It is speculated that tumours e...

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Autores principales: Dart, D Alwyn, Spencer-Dene, Bradley, Gamble, Simon C, Waxman, Jonathan, Bevan, Charlotte L
Formato: Texto
Lenguaje:English
Publicado: Society for Endocrinology 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782800/
https://www.ncbi.nlm.nih.gov/pubmed/19635783
http://dx.doi.org/10.1677/ERC-09-0028
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author Dart, D Alwyn
Spencer-Dene, Bradley
Gamble, Simon C
Waxman, Jonathan
Bevan, Charlotte L
author_facet Dart, D Alwyn
Spencer-Dene, Bradley
Gamble, Simon C
Waxman, Jonathan
Bevan, Charlotte L
author_sort Dart, D Alwyn
collection PubMed
description Current hormonal therapies for prostate cancer are effective initially, but inevitably tumours progress to an advanced, metastatic stage, often referred to as ‘androgen independent’. However, the androgen receptor (AR) signalling pathway is still key for their growth. It is speculated that tumours escape hormonal control via reduction in corepressor proteins. Manipulating such proteins is thus a potential therapeutic strategy to halt or even reverse tumour progression. We aimed to elucidate the effects of altering levels of the AR corepressor and androgen-target protein prohibitin (PHB) on prostate tumour growth. Prostate cancer cells incorporating an integrated androgen-responsive reporter gene and stably expressing vectors to inducibly overexpress or knockdown PHB were generated and used to assess effects on androgen signalling (by real time imaging) and tumour growth both in culture and in vivo. PHB overexpression inhibited AR activity and prostate-specific antigen (PSA) expression as well as androgen-dependent growth of cells, inducing rapid accumulation in G(0)/G(1). Conversely, reduction in PHB increased AR activity, PSA expression, androgen-mediated growth and S-phase entry. In vivo, doxycycline-induced PHB regulation resulted in marked changes in AR activity, and showed significant effects upon tumour growth. Overexpression led to tumour growth arrest and protection from hormonal starvation, whereas RNAi knockdown resulted in accelerated tumour growth, even in castrated mice. This study provides proof of principle that i) reduction in PHB promotes both androgen-dependent and ‘androgen-independent’ tumour growth, and ii) altering AR activity via increasing levels or activity of corepressors is a valid therapeutic strategy for advanced prostate cancer.
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spelling pubmed-27828002009-12-11 Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours Dart, D Alwyn Spencer-Dene, Bradley Gamble, Simon C Waxman, Jonathan Bevan, Charlotte L Endocr Relat Cancer Regular Papers Current hormonal therapies for prostate cancer are effective initially, but inevitably tumours progress to an advanced, metastatic stage, often referred to as ‘androgen independent’. However, the androgen receptor (AR) signalling pathway is still key for their growth. It is speculated that tumours escape hormonal control via reduction in corepressor proteins. Manipulating such proteins is thus a potential therapeutic strategy to halt or even reverse tumour progression. We aimed to elucidate the effects of altering levels of the AR corepressor and androgen-target protein prohibitin (PHB) on prostate tumour growth. Prostate cancer cells incorporating an integrated androgen-responsive reporter gene and stably expressing vectors to inducibly overexpress or knockdown PHB were generated and used to assess effects on androgen signalling (by real time imaging) and tumour growth both in culture and in vivo. PHB overexpression inhibited AR activity and prostate-specific antigen (PSA) expression as well as androgen-dependent growth of cells, inducing rapid accumulation in G(0)/G(1). Conversely, reduction in PHB increased AR activity, PSA expression, androgen-mediated growth and S-phase entry. In vivo, doxycycline-induced PHB regulation resulted in marked changes in AR activity, and showed significant effects upon tumour growth. Overexpression led to tumour growth arrest and protection from hormonal starvation, whereas RNAi knockdown resulted in accelerated tumour growth, even in castrated mice. This study provides proof of principle that i) reduction in PHB promotes both androgen-dependent and ‘androgen-independent’ tumour growth, and ii) altering AR activity via increasing levels or activity of corepressors is a valid therapeutic strategy for advanced prostate cancer. Society for Endocrinology 2009-12 /pmc/articles/PMC2782800/ /pubmed/19635783 http://dx.doi.org/10.1677/ERC-09-0028 Text en © 2009 Society for Endocrinology http://www.endocrinology.org/journals/reuselicence/ This is an Open Access article distributed under the terms of the Society for Endocrinology's Re-use Licence (http://www.endocrinology.org/journals/reuselicence/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Regular Papers
Dart, D Alwyn
Spencer-Dene, Bradley
Gamble, Simon C
Waxman, Jonathan
Bevan, Charlotte L
Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours
title Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours
title_full Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours
title_fullStr Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours
title_full_unstemmed Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours
title_short Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours
title_sort manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours
topic Regular Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782800/
https://www.ncbi.nlm.nih.gov/pubmed/19635783
http://dx.doi.org/10.1677/ERC-09-0028
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