Cisplatin (CDDP) is a widely used agent in the treatment of neuroblastoma. Unfortunately, the development of acquired chemoresistance limits its clinical use. To gain a detailed understanding of the mechanisms underlying the development of such chemoresistance, we comparatively analyzed established cisplatin-resistant neuroblastoma cell line (UKF-NB-4CDDP) and its sensitive counterpart (UKF-NB-4). First, using viability screenings, we confirmed the decreased sensitivity of tested cells to cisplatin and identified a cross-resistance to carboplatin and oxaliplatin. Then, the proteomic signatures were analyzed using nano liquid chromatography with tandem mass spectrometry. Among the proteins responsible for UKF-NB-4CDDP chemoresistance, ion channels transport family proteins, ATP-binding cassette superfamily proteins (ATP = adenosine triphosphate), solute carrier-mediated trans-membrane transporters, proteasome complex subunits, and V-ATPases were identified. Moreover, we detected markedly higher proteasome activity in UKF-NB-4CDDP cells and a remarkable lysosomal enrichment that can be inhibited by bafilomycin A to sensitize UKF-NB-4CDDP to CDDP. Our results indicate that lysosomal sequestration and proteasome activity may be one of the key mechanisms responsible for intrinsic chemoresistance of neuroblastoma to CDDP.

Department of Chemistry and Biochemistry Mendel University in Brno Zemedelska 1 613 00 Brno Czech Republic Central European Institute of Technology Brno University of Technology Purkynova 123 612 00 Brno Czech Republic

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol 5 Uvalu 84 150 06 Prague 5 Czech Republic

Functional Proteomics Department of Molecular Biomedicine and Proteomic Facility Centro de Investigaciones Biológicas Ramiro de Maeztu 9 Madrid 280 40 Spain

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