Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation.

Abstract

Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-eukaryotic translation initiation factor 4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation. Among a series of 23 natural compounds evaluated, silvestrol, which inhibits eIF4A, was identified as being the most growth inhibitory in both primary meningioma and Ben-Men-1 cells. Silvestrol treatment of meningioma cells prominently induced G2/M arrest. Consistently, silvestrol significantly decreased the amounts of cyclins D1, E1, A, and B, PCNA, and Aurora A. In addition, total and phosphorylated AKT, ERK, and FAK, which have been shown to be important drivers for meningioma cell proliferation, were markedly lower in silvestrol-treated Ben-Men-1 cells. Our findings suggest that inhibiting protein translation could be a potential treatment for meningiomas.

• Authors: Janet L Oblinger, Sarah S Burns, Jie Huang, Li Pan, Yulin Ren, Rulong Shen, A Douglas Kinghorn, D Bradley Welling, Long-Sheng Chang
• Journal: Experimental neurology (Exp Neurol) Vol. 299 Issue Pt B Pg. 299-307 (01 2018) ISSN: 1090-2430 [Electronic] United States
• PMID: 28610844 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyclins
• Eukaryotic Initiation Factor-4E
• Eukaryotic Initiation Factor-4G
• Neoplasm Proteins
• Proliferating Cell Nuclear Antigen
• RNA, Small Interfering
• Triterpenes
• silvestrol
• AURKA protein, human
• Aurora Kinase A
• Eukaryotic Initiation Factor-4A

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Aurora Kinase A (biosynthesis, genetics)
• Cyclins (biosynthesis, genetics)
• Drug Screening Assays, Antitumor
• Eukaryotic Initiation Factor-4A (antagonists & inhibitors, biosynthesis, genetics)
• Eukaryotic Initiation Factor-4E (biosynthesis, genetics)
• Eukaryotic Initiation Factor-4G (biosynthesis, genetics)
• Female
• G2 Phase (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Humans
• Male
• Meningeal Neoplasms (drug therapy, genetics, pathology)
• Meningioma (drug therapy, genetics, pathology)
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Peptide Chain Initiation, Translational (drug effects)
• Proliferating Cell Nuclear Antigen (biosynthesis, genetics)
• RNA, Small Interfering (pharmacology)
• Triterpenes (pharmacology, therapeutic use)
• Tumor Cells, Cultured