Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival

Abstract The atypical C-X-C chemokine receptor 7 (CXCR7) has been implicated in supporting aggressive cancer phenotypes in several cancers including prostate cancer. However, the mechanisms driving overexpression of this receptor in cancer are poorly understood. This study investigates the role of a...

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Autores principales:	James J. Hoy, Georgios Kallifatidis, Diandra K. Smith, Bal L. Lokeshwar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d694f9f3e8db41efa65a4e39eb7119d8
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spelling	oai:doaj.org-article:d694f9f3e8db41efa65a4e39eb7119d82021-12-02T11:41:20ZInhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival10.1038/s41598-017-02918-32045-2322https://doaj.org/article/d694f9f3e8db41efa65a4e39eb7119d82017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02918-3https://doaj.org/toc/2045-2322Abstract The atypical C-X-C chemokine receptor 7 (CXCR7) has been implicated in supporting aggressive cancer phenotypes in several cancers including prostate cancer. However, the mechanisms driving overexpression of this receptor in cancer are poorly understood. This study investigates the role of androgen receptor (AR) in regulating CXCR7. Androgen deprivation or AR inhibition significantly increased CXCR7 expression in androgen-responsive prostate cancer cell lines, which was accompanied by enhanced epidermal growth factor receptor (EGFR)-mediated mitogenic signaling, promoting tumor cell survival through an androgen-independent signaling program. Using multiple approaches we demonstrate that AR directly binds to the CXCR7 promoter, suppressing transcription. Clustered regularly interspaced short palindromic repeats (CRISPR) directed Cas9 nuclease-mediated gene editing of CXCR7 revealed that prostate cancer cells depend on CXCR7 for proliferation, survival and clonogenic potential. Loss of CXCR7 expression by CRISPR-Cas9 gene editing resulted in a halt of cell proliferation, severely impaired EGFR signaling and the onset of cellular senescence. Characterization of a mutated CXCR7-expressing LNCaP cell clone showed altered intracellular signaling and reduced spheroid formation potential. Our results demonstrate that CXCR7 is a potential target for adjuvant therapy in combination with androgen deprivation therapy (ADT) to prevent androgen-independent tumor cell survival.James J. HoyGeorgios KallifatidisDiandra K. SmithBal L. LokeshwarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q James J. Hoy Georgios Kallifatidis Diandra K. Smith Bal L. Lokeshwar Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival
description	Abstract The atypical C-X-C chemokine receptor 7 (CXCR7) has been implicated in supporting aggressive cancer phenotypes in several cancers including prostate cancer. However, the mechanisms driving overexpression of this receptor in cancer are poorly understood. This study investigates the role of androgen receptor (AR) in regulating CXCR7. Androgen deprivation or AR inhibition significantly increased CXCR7 expression in androgen-responsive prostate cancer cell lines, which was accompanied by enhanced epidermal growth factor receptor (EGFR)-mediated mitogenic signaling, promoting tumor cell survival through an androgen-independent signaling program. Using multiple approaches we demonstrate that AR directly binds to the CXCR7 promoter, suppressing transcription. Clustered regularly interspaced short palindromic repeats (CRISPR) directed Cas9 nuclease-mediated gene editing of CXCR7 revealed that prostate cancer cells depend on CXCR7 for proliferation, survival and clonogenic potential. Loss of CXCR7 expression by CRISPR-Cas9 gene editing resulted in a halt of cell proliferation, severely impaired EGFR signaling and the onset of cellular senescence. Characterization of a mutated CXCR7-expressing LNCaP cell clone showed altered intracellular signaling and reduced spheroid formation potential. Our results demonstrate that CXCR7 is a potential target for adjuvant therapy in combination with androgen deprivation therapy (ADT) to prevent androgen-independent tumor cell survival.
format	article
author	James J. Hoy Georgios Kallifatidis Diandra K. Smith Bal L. Lokeshwar
author_facet	James J. Hoy Georgios Kallifatidis Diandra K. Smith Bal L. Lokeshwar
author_sort	James J. Hoy
title	Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival
title_short	Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival
title_full	Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival
title_fullStr	Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival
title_full_unstemmed	Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival
title_sort	inhibition of androgen receptor promotes cxc-chemokine receptor 7-mediated prostate cancer cell survival
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d694f9f3e8db41efa65a4e39eb7119d8
work_keys_str_mv	AT jamesjhoy inhibitionofandrogenreceptorpromotescxcchemokinereceptor7mediatedprostatecancercellsurvival AT georgioskallifatidis inhibitionofandrogenreceptorpromotescxcchemokinereceptor7mediatedprostatecancercellsurvival AT diandraksmith inhibitionofandrogenreceptorpromotescxcchemokinereceptor7mediatedprostatecancercellsurvival AT balllokeshwar inhibitionofandrogenreceptorpromotescxcchemokinereceptor7mediatedprostatecancercellsurvival
_version_	1718395429557633024

Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival

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