Zbynek Heger, Berta Casar, Roman Guran, Vladislav Strmiska, Vivian de los Ríos, Miguel Angel Merlos Rodrigo, Yazan Haddad, Vojtech Adam, Piero Crespo, J. Ignacio Casal, Hana Michalkova, Petra Pokorná, Tomas Eckschlager, European Commission, Czech Health Research Council, Czech Science Foundation, Federation of European Biochemical Societies, Ministry of Education, Youth and Sports (Czech Republic), Merlos Rodrigo, Miguel Angel, Strmiska, Vladislav, Casar, Berta, Crespo, Piero, de los Ríos, Vivian, Casal, J. Ignacio, Haddad, Yazan, Guran, Roman, Adam, Vojtech, Merlos Rodrigo, Miguel Angel [0000-0002-1920-0948], Strmiska, Vladislav [0000-0002-7036-1640], Casar, Berta [0000-0002-3058-5631], Crespo, Piero [0000-0003-2825-7783], de los Ríos, Vivian [0000-0001-5582-6879], Casal, J. Ignacio [0000-0003-1085-2840], Haddad, Yazan [0000-0002-7844-4336], Guran, Roman [0000-0002-2912-714X], and Adam, Vojtech [0000-0002-8527-286X]
14 p.-6 fig., Metallothionein-3 has poorly characterized functions in neuroblastoma. Cisplatin-based chemotherapy is a major regimen to treat neuroblastoma, but its clinical efficacy is limited by chemoresistance. We investigated the impact of human metallothionein-3 (hMT3) up-regulation in neuroblastoma cells and the mechanisms underlying the cisplatin-resistance. We confirmed the cisplatin-metallothionein complex formation using mass spectrometry. Overexpression of hMT3 decreased the sensitivity of neuroblastoma UKF-NB-4 cells to cisplatin. We report, for the first time, cisplatin-sensitive human UKF-NB-4 cells remodelled into cisplatin-resistant cells via high and constitutive hMT3 expression in an in vivo model using chick chorioallantoic membrane assay. Comparative proteomic analysis demonstrated that several biological pathways related to apoptosis, transport, proteasome, and cellular stress were involved in cisplatin-resistance in hMT3 overexpressing UKF-NB-4 cells. Overall, our data confirmed that up-regulation of hMT3 positively correlated with increased cisplatin-chemoresistance in neuroblastoma, and a high level of hMT3 could be one of the causes of frequent tumour relapses., The authors gratefully acknowledge to the Proteomics and Genomics Facility (CIB-CSIC), a member of ProteoRed-ISCIII network, for the protein identification by nLC-MS/MS. The authors also acknowledge funding from the European Research Council (ERC) under the European Union´s Horizon 2020 Research and Innovation Programme (grant agreement No. 759585), the Czech Health Research Council (project no. 15-28334A), the Czech Science Foundation (project no. 19-13766J), FEBS—Federation of European Biochemical Societies and under the CEITEC 2020 project (LQ1601) by the Ministry of Education, Youth and Sports of the Czech Republic.