Modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.

<h4>Background</h4>Prostate epithelial cells depend on androgens for survival and function. In (early) prostate cancer (PCa) androgens also regulate tumor growth, which is exploited by hormonal therapies in metastatic disease. The aim of the present study was to characterize the androgen...

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Autores principales:	Rute B Marques, Natasja F Dits, Sigrun Erkens-Schulze, Wilfred F J van Ijcken, Wytske M van Weerden, Guido Jenster
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6c566cb562d24387905e77cc1907a471
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spelling	oai:doaj.org-article:6c566cb562d24387905e77cc1907a4712021-11-18T06:48:38ZModulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.1932-620310.1371/journal.pone.0023144https://doaj.org/article/6c566cb562d24387905e77cc1907a4712011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21829708/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Prostate epithelial cells depend on androgens for survival and function. In (early) prostate cancer (PCa) androgens also regulate tumor growth, which is exploited by hormonal therapies in metastatic disease. The aim of the present study was to characterize the androgen receptor (AR) response in hormonal therapy-resistant PC346 cells and identify potential disease markers.<h4>Methodology/principal findings</h4>Human 19K oligoarrays were used to establish the androgen-regulated expression profile of androgen-responsive PC346C cells and its derivative therapy-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A AR mutation). In total, 107 transcripts were differentially-expressed in PC346C and derivatives after R1881 or hydroxyflutamide stimulations. The AR-regulated expression profiles reflected the AR modifications of respective therapy-resistant sublines: AR overexpression resulted in stronger and broader transcriptional response to R1881 stimulation, AR down-regulation correlated with deficient response of AR-target genes and the T877A mutation resulted in transcriptional response to both R1881 and hydroxyflutamide. This AR-target signature was linked to multiple publicly available cell line and tumor derived PCa databases, revealing that distinct functional clusters were differentially modulated during PCa progression. Differentiation and secretory functions were up-regulated in primary PCa but repressed in metastasis, whereas proliferation, cytoskeletal remodeling and adhesion were overexpressed in metastasis. Finally, the androgen-regulated genes ENDOD1, MCCC2 and ACSL3 were selected as potential disease markers for RT-PCR quantification in a distinct set of human prostate specimens. ENDOD1 and ACSL3 showed down-regulation in high-grade and metastatic PCa, while MCCC2 was overexpressed in low-grade PCa.<h4>Conclusions/significance</h4>AR modifications altered the transcriptional response to (anti)androgens in therapy-resistant cells. Furthermore, selective down-regulation of genes involved in differentiation and up-regulation of genes promoting proliferation and invasion suggest a disturbed balance between the growth and differentiation functions of the AR pathway during PCa progression. These findings may have implications in the current treatment and development of novel therapeutical approaches for metastatic PCa.Rute B MarquesNatasja F DitsSigrun Erkens-SchulzeWilfred F J van IjckenWytske M van WeerdenGuido JensterPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 8, p e23144 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rute B Marques Natasja F Dits Sigrun Erkens-Schulze Wilfred F J van Ijcken Wytske M van Weerden Guido Jenster Modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.
description	<h4>Background</h4>Prostate epithelial cells depend on androgens for survival and function. In (early) prostate cancer (PCa) androgens also regulate tumor growth, which is exploited by hormonal therapies in metastatic disease. The aim of the present study was to characterize the androgen receptor (AR) response in hormonal therapy-resistant PC346 cells and identify potential disease markers.<h4>Methodology/principal findings</h4>Human 19K oligoarrays were used to establish the androgen-regulated expression profile of androgen-responsive PC346C cells and its derivative therapy-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A AR mutation). In total, 107 transcripts were differentially-expressed in PC346C and derivatives after R1881 or hydroxyflutamide stimulations. The AR-regulated expression profiles reflected the AR modifications of respective therapy-resistant sublines: AR overexpression resulted in stronger and broader transcriptional response to R1881 stimulation, AR down-regulation correlated with deficient response of AR-target genes and the T877A mutation resulted in transcriptional response to both R1881 and hydroxyflutamide. This AR-target signature was linked to multiple publicly available cell line and tumor derived PCa databases, revealing that distinct functional clusters were differentially modulated during PCa progression. Differentiation and secretory functions were up-regulated in primary PCa but repressed in metastasis, whereas proliferation, cytoskeletal remodeling and adhesion were overexpressed in metastasis. Finally, the androgen-regulated genes ENDOD1, MCCC2 and ACSL3 were selected as potential disease markers for RT-PCR quantification in a distinct set of human prostate specimens. ENDOD1 and ACSL3 showed down-regulation in high-grade and metastatic PCa, while MCCC2 was overexpressed in low-grade PCa.<h4>Conclusions/significance</h4>AR modifications altered the transcriptional response to (anti)androgens in therapy-resistant cells. Furthermore, selective down-regulation of genes involved in differentiation and up-regulation of genes promoting proliferation and invasion suggest a disturbed balance between the growth and differentiation functions of the AR pathway during PCa progression. These findings may have implications in the current treatment and development of novel therapeutical approaches for metastatic PCa.
format	article
author	Rute B Marques Natasja F Dits Sigrun Erkens-Schulze Wilfred F J van Ijcken Wytske M van Weerden Guido Jenster
author_facet	Rute B Marques Natasja F Dits Sigrun Erkens-Schulze Wilfred F J van Ijcken Wytske M van Weerden Guido Jenster
author_sort	Rute B Marques
title	Modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.
title_short	Modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.
title_full	Modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.
title_fullStr	Modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.
title_full_unstemmed	Modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.
title_sort	modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/6c566cb562d24387905e77cc1907a471
work_keys_str_mv	AT rutebmarques modulationofandrogenreceptorsignalinginhormonaltherapyresistantprostatecancercelllines AT natasjafdits modulationofandrogenreceptorsignalinginhormonaltherapyresistantprostatecancercelllines AT sigrunerkensschulze modulationofandrogenreceptorsignalinginhormonaltherapyresistantprostatecancercelllines AT wilfredfjvanijcken modulationofandrogenreceptorsignalinginhormonaltherapyresistantprostatecancercelllines AT wytskemvanweerden modulationofandrogenreceptorsignalinginhormonaltherapyresistantprostatecancercelllines AT guidojenster modulationofandrogenreceptorsignalinginhormonaltherapyresistantprostatecancercelllines
_version_	1718424355464019968

Modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.

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