title: The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Authors' Affiliations: Laboratori de Recerca Translacional and Servei d'Oncologia Mèdica, Institut Català d'Oncologia, Hospital Duran i Reynals; Servei d'Anatomia Patològica, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat; Departaments de Patologia i Terapèutica Experimental and Ciències Fisiològiques II, Universitat de Barcelona; Institut d'Investigació Biomèdica de Bellvitge (IDIBELL); Laboratori d'Oncologia Molecular and Cancer Epigenetics and Biology Program (PEBC), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Juliachs
authors.forename: C
authors.initials: C
authors.lastname: Muñoz
authors.forename: C A
authors.initials: CA
authors.lastname: Moutinho
authors.forename: A
authors.initials: A
authors.lastname: Vidal
authors.forename: E
authors.initials: E
authors.lastname: Condom
authors.forename: M
authors.initials: M
authors.lastname: Esteller
authors.forename: M
authors.initials: M
authors.lastname: Graupera
authors.forename: O
authors.initials: O
authors.lastname: Casanovas
authors.forename: J R
authors.initials: JR
authors.lastname: Germà
authors.forename: A
authors.initials: A
authors.lastname: Villanueva
authors.forename: F
authors.initials: F
authors.lastname: Viñals
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013736:Testicular Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D020797:Receptor, Platelet-Derived Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D002945:Cisplatin