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

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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.

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American Association for Cancer Research

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(c) American Association for Cancer Research, 2014

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Articles publicats en revistes (Ciències Fisiològiques)

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