The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors

Purpose: we examined whether PI3K-AKT or extracellular signal-regulated kinase (ERK) signaling pathways could play a role in the development of cisplatin (CDDP) resistance in testicular germ cell tumor (TGT) cells. Experimental design: we compared AKT and ERK activation levels in CDDP-sensitive test...

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Autores: Juliachs Milà, Mercè, Muñoz, C., Moutinho, Cátia, Vidal-Bel, August, Condom i Mundó, Enric, Esteller, Manel, Graupera i Garcia-Milà, Mariona, Casanovas i Casanovas, Oriol, Germà Lluch, José Ramón, Villanueva Garatachea, Alberto, Viñals Canals, Francesc
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2014
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/120991
Acceso en línea:https://hdl.handle.net/2445/120991
Access Level:acceso abierto
Palabra clave:Malalties del testicle
Tumors
Càncer
Resistència als medicaments
Medicaments antineoplàstics
Cisplatí
Testis diseases
Cancer
Drug resistance
Antineoplastic agents
Cisplatin
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spelling The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumorsJuliachs Milà, MercèMuñoz, C.Moutinho, CátiaVidal-Bel, AugustCondom i Mundó, EnricEsteller, ManelGraupera i Garcia-Milà, MarionaCasanovas i Casanovas, OriolGermà Lluch, José RamónVillanueva Garatachea, AlbertoViñals Canals, FrancescMalalties del testicleTumorsCàncerResistència als medicamentsMedicaments antineoplàsticsCisplatíTestis diseasesTumorsCancerDrug resistanceAntineoplastic agentsCisplatinPurpose: we examined whether PI3K-AKT or extracellular signal-regulated kinase (ERK) signaling pathways could play a role in the development of cisplatin (CDDP) resistance in testicular germ cell tumor (TGT) cells. Experimental design: we compared AKT and ERK activation levels in CDDP-sensitive testicular tumor cells and in their corresponding CDDP-resistant-derived cells. We also analyzed these pathways in orthotopic testicular tumors and human patient samples. Results: our results indicated that there was overactivation of AKT in CDDP-resistant cells compared with sensitive cells, but no effect on activated ERK levels. We observed an increase in mRNA and protein levels for platelet-derived growth factor (PDGF) receptor β and PDGF-B ligand. These were responsible for AKT overactivation in CDDP-resistant cells. When PDGFRβ levels were decreased by short hairpin RNA (shRNA) treatment or its activation was blocked by pazopanib, CDDP-resistant cells behaved like sensitive cells. Moreover, CDDP-resistant cells were more sensitive to incubation with PDGFRβ inhibitors such as pazopanib or sunitinib than sensitive cells, a finding consistent with these cells being dependent on this signaling pathway. We also found overexpression of PDGFRβ and pAKT in CDDP-resistant choriocarcinoma orthotopic tumor versus their CDDP-sensitive counterparts. Finally, we found high PDGFRβ levels in human testicular tumors, and overexpression in CDDP-resistant testicular choriocarcinomas compared with the CDDP-sensitive and nontreated tumors. Conclusions: the PDGFRβ-AKT pathway plays a critical role in the development of CDDP resistance in testicular tumoral cells.American Association for Cancer Research2018201820142018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion10 p.application/pdfhttps://hdl.handle.net/2445/120991Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1158/1078-0432.CCR-13-1131Clinical Cancer Research, 2014, vol. 20, num. 3, p. 658-667https://doi.org/10.1158/1078-0432.CCR-13-1131(c) American Association for Cancer Research, 2014info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1209912026-05-29T05:05:01Z
dc.title.none.fl_str_mv The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors
title The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors
spellingShingle The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors
Juliachs Milà, Mercè
Malalties del testicle
Tumors
Càncer
Resistència als medicaments
Medicaments antineoplàstics
Cisplatí
Testis diseases
Tumors
Cancer
Drug resistance
Antineoplastic agents
Cisplatin
title_short The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors
title_full The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors
title_fullStr The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors
title_full_unstemmed The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors
title_sort The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors
dc.creator.none.fl_str_mv Juliachs Milà, Mercè
Muñoz, C.
Moutinho, Cátia
Vidal-Bel, August
Condom i Mundó, Enric
Esteller, Manel
Graupera i Garcia-Milà, Mariona
Casanovas i Casanovas, Oriol
Germà Lluch, José Ramón
Villanueva Garatachea, Alberto
Viñals Canals, Francesc
author Juliachs Milà, Mercè
author_facet Juliachs Milà, Mercè
Muñoz, C.
Moutinho, Cátia
Vidal-Bel, August
Condom i Mundó, Enric
Esteller, Manel
Graupera i Garcia-Milà, Mariona
Casanovas i Casanovas, Oriol
Germà Lluch, José Ramón
Villanueva Garatachea, Alberto
Viñals Canals, Francesc
author_role author
author2 Muñoz, C.
Moutinho, Cátia
Vidal-Bel, August
Condom i Mundó, Enric
Esteller, Manel
Graupera i Garcia-Milà, Mariona
Casanovas i Casanovas, Oriol
Germà Lluch, José Ramón
Villanueva Garatachea, Alberto
Viñals Canals, Francesc
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties del testicle
Tumors
Càncer
Resistència als medicaments
Medicaments antineoplàstics
Cisplatí
Testis diseases
Tumors
Cancer
Drug resistance
Antineoplastic agents
Cisplatin
topic Malalties del testicle
Tumors
Càncer
Resistència als medicaments
Medicaments antineoplàstics
Cisplatí
Testis diseases
Tumors
Cancer
Drug resistance
Antineoplastic agents
Cisplatin
description Purpose: we examined whether PI3K-AKT or extracellular signal-regulated kinase (ERK) signaling pathways could play a role in the development of cisplatin (CDDP) resistance in testicular germ cell tumor (TGT) cells. Experimental design: we compared AKT and ERK activation levels in CDDP-sensitive testicular tumor cells and in their corresponding CDDP-resistant-derived cells. We also analyzed these pathways in orthotopic testicular tumors and human patient samples. Results: our results indicated that there was overactivation of AKT in CDDP-resistant cells compared with sensitive cells, but no effect on activated ERK levels. We observed an increase in mRNA and protein levels for platelet-derived growth factor (PDGF) receptor β and PDGF-B ligand. These were responsible for AKT overactivation in CDDP-resistant cells. When PDGFRβ levels were decreased by short hairpin RNA (shRNA) treatment or its activation was blocked by pazopanib, CDDP-resistant cells behaved like sensitive cells. Moreover, CDDP-resistant cells were more sensitive to incubation with PDGFRβ inhibitors such as pazopanib or sunitinib than sensitive cells, a finding consistent with these cells being dependent on this signaling pathway. We also found overexpression of PDGFRβ and pAKT in CDDP-resistant choriocarcinoma orthotopic tumor versus their CDDP-sensitive counterparts. Finally, we found high PDGFRβ levels in human testicular tumors, and overexpression in CDDP-resistant testicular choriocarcinomas compared with the CDDP-sensitive and nontreated tumors. Conclusions: the PDGFRβ-AKT pathway plays a critical role in the development of CDDP resistance in testicular tumoral cells.
publishDate 2014
dc.date.none.fl_str_mv 2014
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/120991
url https://hdl.handle.net/2445/120991
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1158/1078-0432.CCR-13-1131
Clinical Cancer Research, 2014, vol. 20, num. 3, p. 658-667
https://doi.org/10.1158/1078-0432.CCR-13-1131
dc.rights.none.fl_str_mv (c) American Association for Cancer Research, 2014
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Association for Cancer Research, 2014
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 10 p.
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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