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Eukaryotic Translation Initiation Factor 4AI: A Potential Novel Target in Neuroblastoma

Authors :
Christina Skofler
Florian Kleinegger
Stefanie Krassnig
Anna Maria Birkl-Toeglhofer
Georg Singer
Holger Till
Martin Benesch
Regina Cencic
John A. Porco
Jerry Pelletier
Christoph Castellani
Andrea Raicht
Ewa Izycka-Swieszewska
Piotr Czapiewski
Johannes Haybaeck
Source :
Cells, Vol 10, Iss 2, p 301 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Neuroblastoma (NB) is the most common extracranial pediatric solid tumor. Children suffering from high-risk and/or metastatic NB often show no response to therapy, and new therapeutic approaches are urgently needed. Malignant tumor development has been shown to be driven by the dysregulation of eukaryotic initiation factors (eIFs) at the translation initiation. Especially the activity of the heterotrimeric eIF4F complex is often altered in malignant cells, since it is the direct connection to key oncogenic signaling pathways such as the PI3K/AKT/mTOR-pathway. A large body of literature exists that demonstrates targeting the translational machinery as a promising anti-neoplastic approach. The objective of this study was to determine whether eIF4F complex members are aberrantly expressed in NB and whether targeting parts of the complex may be a therapeutic strategy against NB. We show that eIF4AI is overexpressed in NB patient tissue using immunohistochemistry, immunoblotting, and RT-qPCR. NB cell lines exhibit decreased viability, increased apoptosis rates as well as changes in cell cycle distribution when treated with the synthetic rocaglate CR-1-31-B, which clamps eIF4A and eIF4F onto mRNA, resulting in a translational block. Additionally, this study reveals that CR-1-31-B is effective against NB cell lines at low nanomolar doses (≤20 nM), which have been shown to not affect non-malignant cells in previous studies. Thus, our study provides information of the expression status on eIF4AI in NB and offers initial promising insight into targeting translation initiation as an anti-tumorigenic approach for NB.

Details

Language :
English
ISSN :
20734409
Volume :
10
Issue :
2
Database :
Directory of Open Access Journals
Journal :
Cells
Publication Type :
Academic Journal
Accession number :
edsdoj.18f806aa7e4e4295a8c835c5577e2fb8
Document Type :
article
Full Text :
https://doi.org/10.3390/cells10020301