Thiosemicarbazones down-regulate N-Myc expression in neuroblastoma cells via transcriptional and post-translational mechanisms.
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Neuroblastoma (NB) is an aggressive childhood cancer in which the transcription factor N-Myc is a key oncogenic driver. Iron-binding ligands such as desferrioxamine (DFO) suppress N-Myc expression, but the mechanism remains unclear. To examine this, we evaluated the clinically trialed thiosemicarbazone, DpC, which showed potent anti-proliferative activity against NB and compared it to DFO. RNA-sequencing revealed DpC elicited transcriptional changes at ~20-fold lower concentrations than DFO. In NB cells, DFO or DpC up-regulated several N-Myc downstream targets, including the metastasis suppressor, NDRG1, and induced NDRG1 nuclear translocation in three NB cell-types. Both agents significantly decreased N-Myc mRNA and protein in p53-mutant cells (Kelly, BE(2)-C), whereas in SH-SY5Y cells (wild-type p53), DFO caused no significant change in N-Myc mRNA or protein. This result together with its marked efficacy at lower concentrations at down-regulating this key oncoprotein, highlighted the superiority of DpC relative to DFO. In SH-SY5Y cells, silencing studies indicated the p53 target, MDM2, maintained N-Myc mRNA following DFO. The loss of N-Myc protein by the ligands was reversed by the proteasome inhibitor, epoxomicin. Considering the role of the proteasome, silencing the ubiquitin-like modifier-activating enzyme 1 (UBA1), which catalyzes the first step in ubiquitination, implicated a ubiquitin-independent proteasomal process in the activity of DFO and DpC. Collectively, DFO and DpC down-regulate N-Myc in NB cells via combined transcriptional and post-transcriptional mechanisms. DpC demonstrated multiple advantageous properties to DFO, and unlike DFO, is known to be orally active in vivo and simple to synthesize, facilitating its administration and economical production.