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Investigational New Drugs
Published in: Investigational New Drugs 2/2018

01-04-2018 | PRECLINICAL STUDIES

4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma

Authors: Arpita De, Blake A. Jacobson, Mark S. Peterson, Joe Jay-Dixon, Marian G. Kratzke, Ahad A. Sadiq, Manish R. Patel, Robert A. Kratzke

Published in: Investigational New Drugs | Issue 2/2018

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Summary

Deregulation of cap-dependent translation has been implicated in the malignant transformation of numerous human tissues. 4EGI-1, a novel small-molecule inhibitor of cap-dependent translation, disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex. The effects of 4EGI-1-mediated inhibition of translation initiation in malignant pleural mesothelioma (MPM) were examined. 4EGI-1 preferentially inhibited cell viability and induced apoptosis in MPM cells compared to normal mesothelial (LP9) cells. This effect was associated with hypophosphorylation of 4E–binding protein 1 (4E–BP1) and decreased protein levels of the cancer-related genes, c-myc and osteopontin. 4EGI-1 showed enhanced cytotoxicity in combination with pemetrexed or gemcitabine. Translatome-wide polysome microarray analysis revealed a large cohort of genes that were translationally regulated upon treatment with 4EGI-1. The 4EGI-1-regulated translatome was negatively correlated to a previously published translatome regulated by eIF4E overexpression in human mammary epithelial cells, which is in agreement with the notion that 4EGI-1 inhibits the eIF4F complex. These data indicate that inhibition of the eIF4F complex by 4EGI-1 or similar translation inhibitors could be a strategy for treating mesothelioma. Genome wide translational profiling identified a large cohort of promising target genes that should be further evaluated for their potential significance in the treatment of MPM.
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Metadata
Title
4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma
Authors
Arpita De
Blake A. Jacobson
Mark S. Peterson
Joe Jay-Dixon
Marian G. Kratzke
Ahad A. Sadiq
Manish R. Patel
Robert A. Kratzke
Publication date
01-04-2018
Publisher
Springer US
Published in
Investigational New Drugs / Issue 2/2018
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-017-0535-z

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