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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / physiology*
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Male
  • Mice
  • Neoplasms, Germ Cell and Embryonal / genetics
  • Neoplasms, Germ Cell and Embryonal / metabolism*
  • Neoplasms, Germ Cell and Embryonal / pathology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Signal Transduction / physiology*
  • Testicular Neoplasms / genetics
  • Testicular Neoplasms / metabolism*
  • Testicular Neoplasms / pathology
  • Transduction, Genetic
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Receptor, Platelet-Derived Growth Factor beta
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Cisplatin

Supplementary concepts

  • Testicular Germ Cell Tumor