Androgen-induced cell migration: role of androgen receptor/filamin A association.

<h4>Background</h4>Androgen receptor (AR) controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migra...

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Autores principales:	Gabriella Castoria, Loredana D'Amato, Alessandra Ciociola, Pia Giovannelli, Tiziana Giraldi, Leandra Sepe, Giovanni Paolella, Maria Vittoria Barone, Antimo Migliaccio, Ferdinando Auricchio
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a301171e57da4494802ce6195b278c32
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spelling	oai:doaj.org-article:a301171e57da4494802ce6195b278c322021-11-18T06:58:44ZAndrogen-induced cell migration: role of androgen receptor/filamin A association.1932-620310.1371/journal.pone.0017218https://doaj.org/article/a301171e57da4494802ce6195b278c322011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21359179/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Androgen receptor (AR) controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive.<h4>Methodology/principal findings</h4>Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA) at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK), paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility.<h4>Conclusions/significance</h4>The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development and prostate cancer metastasis.Gabriella CastoriaLoredana D'AmatoAlessandra CiociolaPia GiovannelliTiziana GiraldiLeandra SepeGiovanni PaolellaMaria Vittoria BaroneAntimo MigliaccioFerdinando AuricchioPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 2, p e17218 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gabriella Castoria Loredana D'Amato Alessandra Ciociola Pia Giovannelli Tiziana Giraldi Leandra Sepe Giovanni Paolella Maria Vittoria Barone Antimo Migliaccio Ferdinando Auricchio Androgen-induced cell migration: role of androgen receptor/filamin A association.
description	<h4>Background</h4>Androgen receptor (AR) controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive.<h4>Methodology/principal findings</h4>Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA) at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK), paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility.<h4>Conclusions/significance</h4>The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development and prostate cancer metastasis.
format	article
author	Gabriella Castoria Loredana D'Amato Alessandra Ciociola Pia Giovannelli Tiziana Giraldi Leandra Sepe Giovanni Paolella Maria Vittoria Barone Antimo Migliaccio Ferdinando Auricchio
author_facet	Gabriella Castoria Loredana D'Amato Alessandra Ciociola Pia Giovannelli Tiziana Giraldi Leandra Sepe Giovanni Paolella Maria Vittoria Barone Antimo Migliaccio Ferdinando Auricchio
author_sort	Gabriella Castoria
title	Androgen-induced cell migration: role of androgen receptor/filamin A association.
title_short	Androgen-induced cell migration: role of androgen receptor/filamin A association.
title_full	Androgen-induced cell migration: role of androgen receptor/filamin A association.
title_fullStr	Androgen-induced cell migration: role of androgen receptor/filamin A association.
title_full_unstemmed	Androgen-induced cell migration: role of androgen receptor/filamin A association.
title_sort	androgen-induced cell migration: role of androgen receptor/filamin a association.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/a301171e57da4494802ce6195b278c32
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Androgen-induced cell migration: role of androgen receptor/filamin A association.

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