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

Abstract

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.

DOI: 10.1007/s10637-017-0535-z

Cite this paper

@article{De20174EGI1RC, title={4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma}, author={Arpita De and Blake A. Jacobson and Mark S. Peterson and Joe Jay-Dixon and Marian G. Kratzke and Ahad A. Sadiq and Manish R. Patel and Robert Arthur Kratzke}, journal={Investigational New Drugs}, year={2017}, pages={1-13} }