The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.

<h4>Background</h4>Castrate-resistant prostate cancer (CRPC) is a lethal condition in patients receiving androgen deprivation therapy for prostate cancer (PC). Despite numerous studies showing the expression of HIF1α protein under normoxia in PC cell lines, the role of this normoxic HIF1...

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Autores principales:	Weranja K B Ranasinghe, Lin Xiao, Suzana Kovac, Mike Chang, Carine Michiels, Damien Bolton, Arthur Shulkes, Graham S Baldwin, Oneel Patel
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8fdcdc1151e14acaa32d31f37447b1a2
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spelling	oai:doaj.org-article:8fdcdc1151e14acaa32d31f37447b1a22021-11-18T08:01:11ZThe role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.1932-620310.1371/journal.pone.0054251https://doaj.org/article/8fdcdc1151e14acaa32d31f37447b1a22013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23342109/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Castrate-resistant prostate cancer (CRPC) is a lethal condition in patients receiving androgen deprivation therapy for prostate cancer (PC). Despite numerous studies showing the expression of HIF1α protein under normoxia in PC cell lines, the role of this normoxic HIF1α expression in chemo-resistance and migration has not been investigated previously. As no method is currently available to determine which tumors will progress to CRPC, the role of HIF1α in PC and its potential for predicting the development of CRPC was also investigated.<h4>Methods</h4>The effect of HIF1α protein knockdown on chemo-resistance and migration of PC3 cells was assessed by cell counting and Transwell assays, respectively. Translation efficiency of HIF1α mRNA was determined in PC cells using a HIF1α 5'UTR-luciferase construct. Clinical outcomes were correlated following the staining of 100 prostate tumors for HIF1α expression.<h4>Results</h4>The CRPC-like cell lines (PC3 and DU145) expressed more HIF1α protein than an androgen sensitive cell line (LNCaP). Migration rate and chemo-resistance were higher in the PC3 cells and both were decreased when HIF1α expression was reduced. Increased translation of HIF1α mRNA may be responsible for HIF1α overexpression in PC3 cells. Patients whose tumors expressed HIF1α had significantly decreased metastasis-free survival and the patients who were on androgen-deprivation therapy had decreased CRPC-free survival on Kaplan-Meier analysis. On multivariate analysis HIF1α was an independent risk factor for progression to metastatic PC (Hazard ratio (HR) 9.8, p = 0.017) and development of CRPC (HR 10.0, p = 0.021) in patients on androgen-deprivation therapy. Notably the tumors which did not express HIF1α did not metastasize or develop CRPC.<h4>Conclusions</h4>HIF1α is likely to contribute to metastasis and chemo-resistance of CRPC and targeted reduction of HIF1α may increase the responsiveness of CRPCs to chemotherapy. Expression of HIF1α may be a useful screening tool for development of CRPC.Weranja K B RanasingheLin XiaoSuzana KovacMike ChangCarine MichielsDamien BoltonArthur ShulkesGraham S BaldwinOneel PatelPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e54251 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Weranja K B Ranasinghe Lin Xiao Suzana Kovac Mike Chang Carine Michiels Damien Bolton Arthur Shulkes Graham S Baldwin Oneel Patel The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.
description	<h4>Background</h4>Castrate-resistant prostate cancer (CRPC) is a lethal condition in patients receiving androgen deprivation therapy for prostate cancer (PC). Despite numerous studies showing the expression of HIF1α protein under normoxia in PC cell lines, the role of this normoxic HIF1α expression in chemo-resistance and migration has not been investigated previously. As no method is currently available to determine which tumors will progress to CRPC, the role of HIF1α in PC and its potential for predicting the development of CRPC was also investigated.<h4>Methods</h4>The effect of HIF1α protein knockdown on chemo-resistance and migration of PC3 cells was assessed by cell counting and Transwell assays, respectively. Translation efficiency of HIF1α mRNA was determined in PC cells using a HIF1α 5'UTR-luciferase construct. Clinical outcomes were correlated following the staining of 100 prostate tumors for HIF1α expression.<h4>Results</h4>The CRPC-like cell lines (PC3 and DU145) expressed more HIF1α protein than an androgen sensitive cell line (LNCaP). Migration rate and chemo-resistance were higher in the PC3 cells and both were decreased when HIF1α expression was reduced. Increased translation of HIF1α mRNA may be responsible for HIF1α overexpression in PC3 cells. Patients whose tumors expressed HIF1α had significantly decreased metastasis-free survival and the patients who were on androgen-deprivation therapy had decreased CRPC-free survival on Kaplan-Meier analysis. On multivariate analysis HIF1α was an independent risk factor for progression to metastatic PC (Hazard ratio (HR) 9.8, p = 0.017) and development of CRPC (HR 10.0, p = 0.021) in patients on androgen-deprivation therapy. Notably the tumors which did not express HIF1α did not metastasize or develop CRPC.<h4>Conclusions</h4>HIF1α is likely to contribute to metastasis and chemo-resistance of CRPC and targeted reduction of HIF1α may increase the responsiveness of CRPCs to chemotherapy. Expression of HIF1α may be a useful screening tool for development of CRPC.
format	article
author	Weranja K B Ranasinghe Lin Xiao Suzana Kovac Mike Chang Carine Michiels Damien Bolton Arthur Shulkes Graham S Baldwin Oneel Patel
author_facet	Weranja K B Ranasinghe Lin Xiao Suzana Kovac Mike Chang Carine Michiels Damien Bolton Arthur Shulkes Graham S Baldwin Oneel Patel
author_sort	Weranja K B Ranasinghe
title	The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.
title_short	The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.
title_full	The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.
title_fullStr	The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.
title_full_unstemmed	The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.
title_sort	role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/8fdcdc1151e14acaa32d31f37447b1a2
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The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers.

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