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...
| Autores: | , , , , , , , , , , |
|---|---|
| Tipo de documento: | artigo |
| Estado: | Versión aceptada para publicación |
| Data de publicação: | 2014 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositório: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/120991 |
| Acesso em linha: | https://hdl.handle.net/2445/120991 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Malalties del testicle Tumors Càncer Resistència als medicaments Medicaments antineoplàstics Cisplatí Testis diseases Cancer Drug resistance Antineoplastic agents Cisplatin |
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The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumorsJuliachs Milà, MercèMuñoz, C.Moutinho, CátiaVidal-Bel, AugustCondom i Mundó, EnricEsteller, Manel, 1968-Graupera 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 Research2014info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/120991Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió 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:diposit.ub.edu:2445/1209912026-05-27T06:46:51Z |
| 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, 1968- 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, 1968- 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, 1968- 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 |
| 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 |
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:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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