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

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Diagnostic and Research Center for Molecular BioMedicine, Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
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Center for Biomarker Research in Medicine, 8010 Graz, Austria
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Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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Department of Pediatric and Adolescent Surgery, Medical University of Graz, 8036 Graz, Austria
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Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology/Oncology, Medical University of Graz, 8036 Graz, Austria
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McIntyre Medical Sciences Building, Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
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Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA 02215, USA
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Department of Pathology and Neuropathology, Medical University of Gdańsk, 80-211 Gdańsk, Poland
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Department of Pathomorphology, Medical University of Gdańsk, 80-214 Gdańsk, Poland
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Department of Pathology, Medical Faculty, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany
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Department of Pathology, Klinikum Dessau, 06847 Dessau-Rosslau, Germany
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Author to whom correspondence should be addressed.
Academic Editor: Roberta Castriconi
Cells 2021, 10(2), 301; https://doi.org/10.3390/cells10020301
Received: 10 December 2020 / Revised: 24 January 2021 / Accepted: 29 January 2021 / Published: 2 February 2021
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. View Full-Text
Keywords: neuroblastoma; eukaryotic initiation factor 4AI (eIF4AI); rocaglates; CR-1-31-B; SH-SY5Y; Kelly neuroblastoma; eukaryotic initiation factor 4AI (eIF4AI); rocaglates; CR-1-31-B; SH-SY5Y; Kelly
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MDPI and ACS Style

Skofler, C.; Kleinegger, F.; Krassnig, S.; Birkl-Toeglhofer, A.M.; Singer, G.; Till, H.; Benesch, M.; Cencic, R.; Porco, J.A., Jr.; Pelletier, J.; Castellani, C.; Raicht, A.; Izycka-Swieszewska, E.; Czapiewski, P.; Haybaeck, J. Eukaryotic Translation Initiation Factor 4AI: A Potential Novel Target in Neuroblastoma. Cells 2021, 10, 301. https://doi.org/10.3390/cells10020301

AMA Style

Skofler C, Kleinegger F, Krassnig S, Birkl-Toeglhofer AM, Singer G, Till H, Benesch M, Cencic R, Porco JA Jr., Pelletier J, Castellani C, Raicht A, Izycka-Swieszewska E, Czapiewski P, Haybaeck J. Eukaryotic Translation Initiation Factor 4AI: A Potential Novel Target in Neuroblastoma. Cells. 2021; 10(2):301. https://doi.org/10.3390/cells10020301

Chicago/Turabian Style

Skofler, Christina, Florian Kleinegger, Stefanie Krassnig, Anna M. Birkl-Toeglhofer, Georg Singer, Holger Till, Martin Benesch, Regina Cencic, John A. Porco Jr., Jerry Pelletier, Christoph Castellani, Andrea Raicht, Ewa Izycka-Swieszewska, Piotr Czapiewski, and Johannes Haybaeck. 2021. "Eukaryotic Translation Initiation Factor 4AI: A Potential Novel Target in Neuroblastoma" Cells 10, no. 2: 301. https://doi.org/10.3390/cells10020301

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