Proteomic Signature of Neuroblastoma Cells UKF-NB-4 Reveals Key Role of Lysosomal Sequestration and the Proteasome Complex in Acquiring Chemoresistance to Cisplatin.
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.
['Merlos Rodrigo|Miguel Angel|MA|0000-0002-1920-0948', 'Buchtelova|Hana|H|', 'de Los Rios|Vivian|V|', 'Casal|José Ignacio|JI|0000-0003-1085-2840', 'Eckschlager|Tomas|T|', 'Hrabeta|Jan|J|', 'Belhajova|Marie|M|', 'Heger|Zbynek|Z|', 'Adam|Vojtech|V|0000-0002-8527-286X']
D017209:Apoptosis D045744:Cell Line, Tumor D049109:Cell Proliferation D002945:Cisplatin D019008:Drug Resistance, Neoplasm D015972:Gene Expression Regulation, Neoplastic D006801:Humans D008247:Lysosomes D009447:Neuroblastoma D046988:Proteasome Endopeptidase Complex D040901:Proteomics D059467:Transcriptome
proteomics neuroblastoma lysosomes chemoresistance cisplatin V-ATPases