Universität zu Köln

Montemurro, Luca ORCID: 0000-0002-3802-0846, Raieli, Salvatore ORCID: 0000-0001-7196-7815, Angelucci, Silvia, Bartolucci, Damiano, Amadesi, Camilla, Lampis, Silvia, Scardovi, Anna Lisa, Venturelli, Leonardo ORCID: 0000-0002-9708-8170, Nieddu, Giammario, Cerisoli, Lucia, Fischer, Matthias, Teti, Gabriella, Falconi, Mirella, Pession, Andrea, Hrelia, Patrizia and Tonelli, Roberto (2019). A Novel MYCN-Specific Antigene Oligonucleotide Deregulates Mitochondria and Inhibits Tumor Growth in MYCN-Amplified Neuroblastoma. Cancer Res., 79 (24). S. 6166 - 6178. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Montemurro, Luca UNSPECIFIED orcid.org/0000-0002-3802-0846 UNSPECIFIED Raieli, Salvatore UNSPECIFIED orcid.org/0000-0001-7196-7815 UNSPECIFIED Angelucci, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartolucci, Damiano UNSPECIFIED UNSPECIFIED UNSPECIFIED Amadesi, Camilla UNSPECIFIED UNSPECIFIED UNSPECIFIED Lampis, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Scardovi, Anna Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Venturelli, Leonardo UNSPECIFIED orcid.org/0000-0002-9708-8170 UNSPECIFIED Nieddu, Giammario UNSPECIFIED UNSPECIFIED UNSPECIFIED Cerisoli, Lucia UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Teti, Gabriella UNSPECIFIED UNSPECIFIED UNSPECIFIED Falconi, Mirella UNSPECIFIED UNSPECIFIED UNSPECIFIED Pession, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Hrelia, Patrizia UNSPECIFIED UNSPECIFIED UNSPECIFIED Tonelli, Roberto UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-124356
DOI:	10.1158/0008-5472.CAN-19-0008
Journal or Publication Title:	Cancer Res.
Volume:	79
Number:	24
Page Range:	S. 6166 - 6178
Date:	2019
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language N-MYC; CHROMOSOMAL DNA; EXPRESSION; CELLS; AMPLIFICATION; TRANSCRIPTION; ASSOCIATION; METABOLISM; ACTIVATION; MORPHOLOGY Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12435