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

• Main 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
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: Cells
• Subjects: neuroblastoma; eukaryotic initiation factor 4AI (eIF4AI); rocaglates; CR-1-31-B; SH-SY5Y; Kelly
• Online Access: https://www.mdpi.com/2073-4409/10/2/301

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 previous studies have been shown do not affect non-malignant cells. 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.