Author:
Rodrigo Miguel Angel Merlos,Michalkova Hana,Strmiska Vladislav,Casar Berta,Crespo Piero,de los Rios Vivian,Ignacio Casal J.,Haddad Yazan,Guran Roman,Eckschlager Tomas,Pokorna Petra,Heger Zbynek,Adam Vojtech
Abstract
AbstractMetallothionein-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.
Funder
Agentura Pro Zdravotnický Výzkum České Republiky
Grantová Agentura České Republiky
Ministerstvo Školství, Mládeže a Tělovýchovy
European Research Council
Publisher
Springer Science and Business Media LLC
Cited by
15 articles.
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