Cancer research | 2019
A novel MYCN-specific antigene oligonucleotide deregulates mitochondria and inhibits tumor growth in MYCN-amplified Neuroblastoma.
Abstract
Approximately half of high-risk neuroblastoma (NB) is characterized by MYCN-amplification. N-Myc promotes tumor progression by inducing cell growth and inhibiting differentiation. MYCN has also been shown to play an active role in mitochondrial metabolism, but this relationship is not well understood. While N-myc is a known driver of the disease, it remains a target for which no therapeutic drug exists. Here, we evaluated a novel MYCN-specific antigene PNA oligonucleotide (BGA002) in MYCN-amplified (MNA) or MYCN-expressing NB, and investigated the mechanism of its anti-tumor activity. MYCN mRNA and cell viability were reduced in a broad set of NB cell lines following BGA002 treatment. Furthermore, BGA002 decreased N-myc protein levels and apoptosis in MNA-NB. Analysis of gene expression data from neuroblastoma patients revealed that MYCN was associated with increased reactive oxygen species (ROS), downregulated mitophagy and poor prognosis. Inhibition of MYCN caused profound mitochondrial damage in MNA-NB cells through downregulation of the mitochondrial molecular chaperone TRAP1, which subsequently increased ROS. Correspondigly, inhibition of MYCN reactivated mitophagy. Systemic administration of BGA002 downregulated N-myc and TRAP1 with a concomitant decrease in MNA-NB xenograft tumor weight. In conclusion, this study highlights the role of N-myc in blocking mitophagy in NB and in conferring protection to ROS in mitochondria through upregulation of TRAP1. BGA002 is a potently improved MYCN-specific antigene oligonucleotide that reverts N-myc dysregulated mitochondrial pathways, leading to loss of the protective effect of N-myc against mitochondrial ROS.