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Clin Cancer Res. 2014 Feb 1;20(3):658-67. doi: 10.1158/1078-0432.CCR-13-1131. Epub 2013 Nov 25.

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

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  • 1Authors' 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.

Abstract

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.

©2013 AACR.

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