Antitumor activity of sustained N-myc reduction in rhabdomyosarcomas and transcriptional block by antigene therapy.

Details

Serval ID
serval:BIB_3A83CD7D142B
Type
Article: article from journal or magazin.
Collection
Publications
Title
Antitumor activity of sustained N-myc reduction in rhabdomyosarcomas and transcriptional block by antigene therapy.
Journal
Clinical cancer research
Author(s)
Tonelli R., McIntyre A., Camerin C., Walters Z.S., Di Leo K., Selfe J., Purgato S., Missiaglia E., Tortori A., Renshaw J., Astolfi A., Taylor K.R., Serravalle S., Bishop R., Nanni C., Valentijn L.J., Faccini A., Leuschner I., Formica S., Reis-Filho J.S., Ambrosini V., Thway K., Franzoni M., Summersgill B., Marchelli R., Hrelia P., Cantelli-Forti G., Fanti S., Corradini R., Pession A., Shipley J.
ISSN
1557-3265 (Electronic)
ISSN-L
1078-0432
Publication state
Published
Issued date
01/02/2012
Peer-reviewed
Oui
Volume
18
Number
3
Pages
796-807
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Rhabdomyosarcomas are a major cause of cancer death in children, described with MYCN amplification and, in the alveolar subtype, transcription driven by the PAX3-FOXO1 fusion protein. Our aim was to determine the prevalence of N-Myc protein expression and the potential therapeutic effects of reducing expression in rhabdomyosarcomas, including use of an antigene strategy that inhibits transcription.
Protein expression was assessed by immunohistochemistry. MYCN expression was reduced in representative cell lines by RNA interference and an antigene peptide nucleic acid (PNA) oligonucleotide conjugated to a nuclear localization signal peptide. Associated gene expression changes, cell viability, and apoptosis were analyzed in vitro. As a paradigm for antigene therapy, the effects of systemic treatment of mice with rhabdomyosarcoma cell line xenografts were determined.
High N-Myc levels were significantly associated with genomic amplification, presence of the PAX3/7-FOXO1 fusion genes, and proliferative capacity. Sustained reduction of N-Myc levels in all rhabdomyosarcoma cell lines that express the protein decreased cell proliferation and increased apoptosis. Positive feedback was shown to regulate PAX3-FOXO1 and N-Myc levels in the alveolar subtype that critically decrease PAX3-FOXO1 levels on reducing N-Myc. Pharmacologic systemic administration of the antigene PNA can eliminate alveolar rhabdomyosarcoma xenografts in mice, without relapse or toxicity.
N-Myc, with its restricted expression in non-fetal tissues, is a therapeutic target to treat rhabdomyosarcomas, and blocking gene transcription using antigene oligonucleotide strategies has therapeutic potential in the treatment of cancer and other diseases that has not been previously realized in vivo.
Keywords
Animals, Apoptosis/drug effects, Blotting, Western, Cell Line, Tumor, Electrophoretic Mobility Shift Assay, Gene Dosage, Genes, myc/genetics, Genetic Therapy/methods, Humans, Immunohistochemistry, In Situ Nick-End Labeling, Mice, Mice, Nude, N-Myc Proto-Oncogene Protein, Nuclear Proteins/genetics, Oncogene Proteins/genetics, Oncogene Proteins, Fusion/biosynthesis, Oncogene Proteins, Fusion/genetics, Paired Box Transcription Factors/biosynthesis, Paired Box Transcription Factors/genetics, Peptide Nucleic Acids/pharmacology, Proto-Oncogene Proteins c-myc/biosynthesis, Proto-Oncogene Proteins c-myc/genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Rhabdomyosarcoma/genetics, Rhabdomyosarcoma/therapy, Transcription, Genetic, Xenograft Model Antitumor Assays
Pubmed
Web of science
Create date
26/09/2023 9:53
Last modification date
04/10/2023 14:22
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