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oai:recercat.cat:2445/1209912025-12-05T09:33:52Zcom_2072_1057col_2072_478799col_2072_478916col_2072_478917col_2072_478929

urn:hdl:2445/120991 The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors 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 Malalties del testicle Tumors Càncer Resistència als medicaments Medicaments antineoplàstics Cisplatí Testis diseases Tumors Cancer Drug resistance Antineoplastic agents Cisplatin 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. 2018-03-22T10:43:30Z 2018-03-22T10:43:30Z 2014-02 2018-03-22T10:43:31Z info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion 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 (c) American Association for Cancer Research, 2014 info:eu-repo/semantics/openAccess American Association for Cancer Research Articles publicats en revistes (Ciències Fisiològiques)