Hypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.

In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor progno...

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Autores principales:	Kathrine Røe, Åse Bratland, Ljiljana Vlatkovic, Harald Bull Ragnum, Marie Grøn Saelen, Dag Rune Olsen, Laure Marignol, Anne Hansen Ree
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/17199364992041ea834ef7596d33118e
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spelling	oai:doaj.org-article:17199364992041ea834ef7596d33118e2021-11-18T07:46:05ZHypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.1932-620310.1371/journal.pone.0063723https://doaj.org/article/17199364992041ea834ef7596d33118e2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23675504/?tool=EBIhttps://doaj.org/toc/1932-6203In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naïve, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naïve or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein.Kathrine RøeÅse BratlandLjiljana VlatkovicHarald Bull RagnumMarie Grøn SaelenDag Rune OlsenLaure MarignolAnne Hansen ReePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e63723 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kathrine Røe Åse Bratland Ljiljana Vlatkovic Harald Bull Ragnum Marie Grøn Saelen Dag Rune Olsen Laure Marignol Anne Hansen Ree Hypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.
description	In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naïve, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naïve or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein.
format	article
author	Kathrine Røe Åse Bratland Ljiljana Vlatkovic Harald Bull Ragnum Marie Grøn Saelen Dag Rune Olsen Laure Marignol Anne Hansen Ree
author_facet	Kathrine Røe Åse Bratland Ljiljana Vlatkovic Harald Bull Ragnum Marie Grøn Saelen Dag Rune Olsen Laure Marignol Anne Hansen Ree
author_sort	Kathrine Røe
title	Hypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.
title_short	Hypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.
title_full	Hypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.
title_fullStr	Hypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.
title_full_unstemmed	Hypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.
title_sort	hypoxic tumor kinase signaling mediated by stat5a in development of castration-resistant prostate cancer.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/17199364992041ea834ef7596d33118e
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Hypoxic tumor kinase signaling mediated by STAT5A in development of castration-resistant prostate cancer.

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