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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Published inClinical cancer research
Main Authors 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
Format Journal Article
LanguageEnglish
Published American Association for Cancer Research 01.02.2014
Subjects
Antineoplastic agents
Cancer
Cisplatin
Cisplatí
Càncer
Drug resistance
Malalties del testicle
Medicaments antineoplàstics
Resistència als medicaments
Testis diseases
Tumors
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Summary: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.
ISSN:1078-0432