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

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.

High Expression of EIF4G2 Mediated by the TUG1/Hsa-miR-26a-5p Axis Is Associated with Poor Prognosis and Immune Infiltration of Gastric Cancer

“…The function of eukaryotic translation initiation factors (eIFs) in tumorigenesis has been widely studied. Studies have shown that eIFs are highly expressed in many malignant tumors [6][7][8]. Eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) is a member of the eIF family, which plays a vital role in regulating protein translation [9][10][11].…”

Reanalysis of ribosome profiling datasets reveals a function of rocaglamide A in perturbing the dynamics of translation elongation via eIF4A

“…Rocaglates, for example rocaglamide A (RocA), are a class of natural products isolated from the plant genus Aglaia, which are characterized by a common cyclopenta[b]benzofuran skeleton 24,25 . RocA and many of its derivatives have been demonstrated to be potent antitumor drugs in hematological and solid tumor cancers 24,[26][27][28][29][30][31] . Interestingly, some rocaglates can kill tumor cells while showing no or little toxicity to primary T or B cells and heathy spleen and liver tissues in mouse models, thereby making it an attractive candidate for applications in clinical oncology 24,26,28,[32][33][34] .…”

Genetic and Histopathological Heterogeneity of Neuroblastoma and Precision Therapeutic Approaches for Extremely Unfavorable Histology Subgroups

“…Rocaglamide has been shown to downregulate MYC expression [ 108 ]. CR-1-31B (CR-31) is a synthetic rocaglate [ 106 ]; when treated with CR-1-31-B at low nanomolar doses (≤20 nM), neuroblastoma cell lines exhibit decreased viability and increased apoptosis rates, as well as changes in cell cycle distribution [ 109 ]. These could be attributed to down-regulation of MYC and MYCN by CR-1-31-B.…”