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A Novel MYCN-Specific Antigene Oligonucleotide Deregulates Mitochondria and Inhibits Tumor Growth in MYCN-Amplified Neuroblastoma.
- Source :
-
Cancer research [Cancer Res] 2019 Dec 15; Vol. 79 (24), pp. 6166-6177. Date of Electronic Publication: 2019 Oct 15. - Publication Year :
- 2019
-
Abstract
- Approximately half of high-risk neuroblastoma 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. Although 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 neuroblastoma and investigated the mechanism of its antitumor activity. MYCN mRNA and cell viability were reduced in a broad set of neuroblastoma cell lines following BGA002 treatment. Furthermore, BGA002 decreased N-Myc protein levels and apoptosis in MNA neuroblastoma. Analysis of gene expression data from patients with neuroblastoma 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 neuroblastoma cells through downregulation of the mitochondrial molecular chaperone TRAP1, which subsequently increased ROS. Correspondingly, inhibition of MYCN reactivated mitophagy. Systemic administration of BGA002 downregulated N-Myc and TRAP1, with a concomitant decrease in MNA neuroblastoma xenograft tumor weight. In conclusion, this study highlights the role of N-Myc in blocking mitophagy in neuroblastoma 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. SIGNIFICANCE: A second generation antigene peptide oligonucleotide targeting MYCN induces mitochondrial damage and inhibits growth of MYCN-amplified neuroblastoma cells.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Adolescent
Adult
Animals
Apoptosis drug effects
Cell Differentiation drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Child
Child, Preschool
Female
HSP90 Heat-Shock Proteins metabolism
Humans
Infant
Infant, Newborn
Kaplan-Meier Estimate
Male
Mice
Mitochondria metabolism
Mitochondria pathology
Mitophagy drug effects
N-Myc Proto-Oncogene Protein antagonists & inhibitors
N-Myc Proto-Oncogene Protein genetics
Neuroblastoma drug therapy
Neuroblastoma genetics
Neuroblastoma mortality
Peptide Nucleic Acids genetics
Peptide Nucleic Acids therapeutic use
Prognosis
RNA, Messenger genetics
RNA, Messenger metabolism
Reactive Oxygen Species metabolism
Xenograft Model Antitumor Assays
Young Adult
Gene Expression Regulation, Neoplastic drug effects
Mitochondria drug effects
N-Myc Proto-Oncogene Protein metabolism
Neuroblastoma pathology
Peptide Nucleic Acids pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 79
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 31615807
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-19-0008