期刊
JOURNAL OF PROTEOME RESEARCH
卷 18, 期 3, 页码 1255-1263出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.8b00867
关键词
neuroblastoma; chemoresistance; cisplatin; lysosomes; proteomics; V-ATPases
资金
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [759585]
- AZV Project [15-28334A]
- ERASMUS + Staff Mobility from European Commission
- Ministry of Health of the Czech Republic [00064203]
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-4(CDDP)) 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-4(CDDP) 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-4(CDDP) cells and a remarkable lysosomal enrichment that can be inhibited by bafilomycin A to sensitize UKF-NB-4(CDDP) 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.
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