Human metallothionein-3 (hMT-3), also known as growth inhibitory factor, is predominantly expressed in the central nervous system. hMT-3 is presumed to participate in the processes of heavy metal detoxification, regulation of metabolism and protection against oxidative damage of free radicals in the central nervous system; thus, it could play important neuromodulatory and neuroprotective roles. However, the primary functions of hMT-3 and the mechanism underlying its multiple functions in neuroblastoma have not been elucidated so far. First, we confirmed relatively high expression of hMT-3 encoding mRNA in biopsies (n= 23) from high-risk neuroblastoma subjects. Therefore, we focused on investigation of the impact of hMT-3 up-regulation inN-Mycamplifying neuroblastoma cells. The differentially up-regulated genes involved in biological pathways related to cellular senescence and cell cycle were identified using electrochemical microarray with consequent bioinformatic processing. Further, as experimental verification of microarray data, the cytotoxicity of the cisplatin (CDDP) was examined in hMT-3 and mock cells by MTT and clonogenic assays. Overall, our data strongly suggest that up-regulation of hMT-3 positively correlates with the genes involved in oncogene-induced senescence (CDKN2BandANAPC5) or apoptosis (CASP4). Moreover, we identified a significant increase in chemoresistance to cisplatin (CDDP) due to hMT-3 up-regulation (24IC50: 7.5vs. 19.8 μg/ml), indicating its multipurpose biological significance.

Department of Biochemistry Faculty of Science Charles University CZ 128 40 Prague 2 Czech Republic

Department of Chemistry and Biochemistry Mendel University in Brno CZ 613 00 Brno Czech Republic Central European Institute of Technology Brno University of Technology CZ 616 00 Brno Czech Republic

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

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