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Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells

The functions of androgen receptor (AR) in stromal cells are still debated in spite of the demonstrated importance of these cells in organ development and diseases. Here, we show that physiological androgen concentration (10 nM R1881 or DHT) fails to induce DNA synthesis, while it consistently stimu...

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Autores principales: Castoria, G, Giovannelli, P, Di Donato, M, Ciociola, A, Hayashi, R, Bernal, F, Appella, E, Auricchio, F, Migliaccio, A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649827/
https://www.ncbi.nlm.nih.gov/pubmed/25476896
http://dx.doi.org/10.1038/cddis.2014.497
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author Castoria, G
Giovannelli, P
Di Donato, M
Ciociola, A
Hayashi, R
Bernal, F
Appella, E
Auricchio, F
Migliaccio, A
author_facet Castoria, G
Giovannelli, P
Di Donato, M
Ciociola, A
Hayashi, R
Bernal, F
Appella, E
Auricchio, F
Migliaccio, A
author_sort Castoria, G
collection PubMed
description The functions of androgen receptor (AR) in stromal cells are still debated in spite of the demonstrated importance of these cells in organ development and diseases. Here, we show that physiological androgen concentration (10 nM R1881 or DHT) fails to induce DNA synthesis, while it consistently stimulates cell migration in mesenchymal and transformed mesenchymal cells. Ten nanomolar R1881 triggers p27 Ser10 phosphorylation and its stabilization in NIH3T3 fibroblasts. Activation of Rac and its downstream effector DYRK 1B is responsible for p27 Ser10 phosphorylation and cell quiescence. Ten nanomolar androgen also inhibits transformation induced by oncogenic Ras in NIH3T3 fibroblasts. Overexpression of an AR mutant unable to interact with filamin A, use of a small peptide displacing AR/filamin A interaction, and filamin A knockdown indicate that the androgen-triggered AR/filamin A complex regulates the pathway leading to p27 Ser10 phosphorylation and cell cycle arrest. As the AR/filamin A complex is also responsible for migration stimulated by 10 nM androgen, our report shows that the androgen-triggered AR/filamin A complex controls, through Rac 1, the decision of cells to halt cell cycle and migration. This study reveals a new and unexpected role of androgen/AR signalling in coordinating stromal cell functions.
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spelling pubmed-46498272015-12-02 Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells Castoria, G Giovannelli, P Di Donato, M Ciociola, A Hayashi, R Bernal, F Appella, E Auricchio, F Migliaccio, A Cell Death Dis Original Article The functions of androgen receptor (AR) in stromal cells are still debated in spite of the demonstrated importance of these cells in organ development and diseases. Here, we show that physiological androgen concentration (10 nM R1881 or DHT) fails to induce DNA synthesis, while it consistently stimulates cell migration in mesenchymal and transformed mesenchymal cells. Ten nanomolar R1881 triggers p27 Ser10 phosphorylation and its stabilization in NIH3T3 fibroblasts. Activation of Rac and its downstream effector DYRK 1B is responsible for p27 Ser10 phosphorylation and cell quiescence. Ten nanomolar androgen also inhibits transformation induced by oncogenic Ras in NIH3T3 fibroblasts. Overexpression of an AR mutant unable to interact with filamin A, use of a small peptide displacing AR/filamin A interaction, and filamin A knockdown indicate that the androgen-triggered AR/filamin A complex regulates the pathway leading to p27 Ser10 phosphorylation and cell cycle arrest. As the AR/filamin A complex is also responsible for migration stimulated by 10 nM androgen, our report shows that the androgen-triggered AR/filamin A complex controls, through Rac 1, the decision of cells to halt cell cycle and migration. This study reveals a new and unexpected role of androgen/AR signalling in coordinating stromal cell functions. Nature Publishing Group 2014-12 2014-12-04 /pmc/articles/PMC4649827/ /pubmed/25476896 http://dx.doi.org/10.1038/cddis.2014.497 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0
spellingShingle Original Article
Castoria, G
Giovannelli, P
Di Donato, M
Ciociola, A
Hayashi, R
Bernal, F
Appella, E
Auricchio, F
Migliaccio, A
Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells
title Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells
title_full Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells
title_fullStr Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells
title_full_unstemmed Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells
title_short Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells
title_sort role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649827/
https://www.ncbi.nlm.nih.gov/pubmed/25476896
http://dx.doi.org/10.1038/cddis.2014.497
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