Endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells.

<h4>Background</h4>The endothelin B receptor (ET(B)R) promotes tumorigenesis and melanoma progression through activation by endothelin (ET)-1, thus representing a promising therapeutic target. The stability of hypoxia-inducible factor (HIF)-1alpha is essential for melanomagenesis and pro...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Francesca Spinella, Laura Rosanò, Martina Del Duca, Valeriana Di Castro, Maria Rita Nicotra, Pier Giorgio Natali, Anna Bagnato
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c24fb6c15afe43e3b03640a8f22c5992
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:c24fb6c15afe43e3b03640a8f22c5992
record_format	dspace
spelling	oai:doaj.org-article:c24fb6c15afe43e3b03640a8f22c59922021-12-02T20:20:39ZEndothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells.1932-620310.1371/journal.pone.0011241https://doaj.org/article/c24fb6c15afe43e3b03640a8f22c59922010-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20574527/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The endothelin B receptor (ET(B)R) promotes tumorigenesis and melanoma progression through activation by endothelin (ET)-1, thus representing a promising therapeutic target. The stability of hypoxia-inducible factor (HIF)-1alpha is essential for melanomagenesis and progression, and is controlled by site-specific hydroxylation carried out by HIF-prolyl hydroxylase domain (PHD) and subsequent proteosomal degradation.<h4>Principal findings</h4>Here we found that in melanoma cells ET-1, ET-2, and ET-3 through ET(B)R, enhance the expression and activity of HIF-1alpha and HIF-2alpha that in turn regulate the expression of vascular endothelial growth factor (VEGF) in response to ETs or hypoxia. Under normoxic conditions, ET-1 controls HIF-alpha stability by inhibiting its degradation, as determined by impaired degradation of a reporter gene containing the HIF-1alpha oxygen-dependent degradation domain encompassing the PHD-targeted prolines. In particular, ETs through ET(B)R markedly decrease PHD2 mRNA and protein levels and promoter activity. In addition, activation of phosphatidylinositol 3-kinase (PI3K)-dependent integrin linked kinase (ILK)-AKT-mammalian target of rapamycin (mTOR) pathway is required for ET(B)R-mediated PHD2 inhibition, HIF-1alpha, HIF-2alpha, and VEGF expression. At functional level, PHD2 knockdown does not further increase ETs-induced in vitro tube formation of endothelial cells and melanoma cell invasiveness, demonstrating that these processes are regulated in a PHD2-dependent manner. In human primary and metastatic melanoma tissues as well as in cell lines, that express high levels of HIF-1alpha, ET(B)R expression is associated with low PHD2 levels. In melanoma xenografts, ET(B)R blockade by ET(B)R antagonist results in a concomitant reduction of tumor growth, angiogenesis, HIF-1alpha, and HIF-2alpha expression, and an increase in PHD2 levels.<h4>Conclusions</h4>In this study we identified the underlying mechanism by which ET-1, through the regulation of PHD2, controls HIF-1alpha stability and thereby regulates angiogenesis and melanoma cell invasion. These results further indicate that targeting ET(B)R may represent a potential therapeutic treatment of melanoma by impairing HIF-1alpha stability.Francesca SpinellaLaura RosanòMartina Del DucaValeriana Di CastroMaria Rita NicotraPier Giorgio NataliAnna BagnatoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 6, p e11241 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Francesca Spinella Laura Rosanò Martina Del Duca Valeriana Di Castro Maria Rita Nicotra Pier Giorgio Natali Anna Bagnato Endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells.
description	<h4>Background</h4>The endothelin B receptor (ET(B)R) promotes tumorigenesis and melanoma progression through activation by endothelin (ET)-1, thus representing a promising therapeutic target. The stability of hypoxia-inducible factor (HIF)-1alpha is essential for melanomagenesis and progression, and is controlled by site-specific hydroxylation carried out by HIF-prolyl hydroxylase domain (PHD) and subsequent proteosomal degradation.<h4>Principal findings</h4>Here we found that in melanoma cells ET-1, ET-2, and ET-3 through ET(B)R, enhance the expression and activity of HIF-1alpha and HIF-2alpha that in turn regulate the expression of vascular endothelial growth factor (VEGF) in response to ETs or hypoxia. Under normoxic conditions, ET-1 controls HIF-alpha stability by inhibiting its degradation, as determined by impaired degradation of a reporter gene containing the HIF-1alpha oxygen-dependent degradation domain encompassing the PHD-targeted prolines. In particular, ETs through ET(B)R markedly decrease PHD2 mRNA and protein levels and promoter activity. In addition, activation of phosphatidylinositol 3-kinase (PI3K)-dependent integrin linked kinase (ILK)-AKT-mammalian target of rapamycin (mTOR) pathway is required for ET(B)R-mediated PHD2 inhibition, HIF-1alpha, HIF-2alpha, and VEGF expression. At functional level, PHD2 knockdown does not further increase ETs-induced in vitro tube formation of endothelial cells and melanoma cell invasiveness, demonstrating that these processes are regulated in a PHD2-dependent manner. In human primary and metastatic melanoma tissues as well as in cell lines, that express high levels of HIF-1alpha, ET(B)R expression is associated with low PHD2 levels. In melanoma xenografts, ET(B)R blockade by ET(B)R antagonist results in a concomitant reduction of tumor growth, angiogenesis, HIF-1alpha, and HIF-2alpha expression, and an increase in PHD2 levels.<h4>Conclusions</h4>In this study we identified the underlying mechanism by which ET-1, through the regulation of PHD2, controls HIF-1alpha stability and thereby regulates angiogenesis and melanoma cell invasion. These results further indicate that targeting ET(B)R may represent a potential therapeutic treatment of melanoma by impairing HIF-1alpha stability.
format	article
author	Francesca Spinella Laura Rosanò Martina Del Duca Valeriana Di Castro Maria Rita Nicotra Pier Giorgio Natali Anna Bagnato
author_facet	Francesca Spinella Laura Rosanò Martina Del Duca Valeriana Di Castro Maria Rita Nicotra Pier Giorgio Natali Anna Bagnato
author_sort	Francesca Spinella
title	Endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells.
title_short	Endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells.
title_full	Endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells.
title_fullStr	Endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells.
title_full_unstemmed	Endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells.
title_sort	endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/c24fb6c15afe43e3b03640a8f22c5992
work_keys_str_mv	AT francescaspinella endothelin1inhibitsprolylhydroxylasedomain2toactivatehypoxiainduciblefactor1alphainmelanomacells AT laurarosano endothelin1inhibitsprolylhydroxylasedomain2toactivatehypoxiainduciblefactor1alphainmelanomacells AT martinadelduca endothelin1inhibitsprolylhydroxylasedomain2toactivatehypoxiainduciblefactor1alphainmelanomacells AT valerianadicastro endothelin1inhibitsprolylhydroxylasedomain2toactivatehypoxiainduciblefactor1alphainmelanomacells AT mariaritanicotra endothelin1inhibitsprolylhydroxylasedomain2toactivatehypoxiainduciblefactor1alphainmelanomacells AT piergiorgionatali endothelin1inhibitsprolylhydroxylasedomain2toactivatehypoxiainduciblefactor1alphainmelanomacells AT annabagnato endothelin1inhibitsprolylhydroxylasedomain2toactivatehypoxiainduciblefactor1alphainmelanomacells
_version_	1718374189167017984

Endothelin-1 inhibits prolyl hydroxylase domain 2 to activate hypoxia-inducible factor-1alpha in melanoma cells.

Ejemplares similares