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

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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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Acknowledgements

This work is supported by a generous grant from the Mesothelioma Applied Research Foundation and is dedicated to the memory of Christopher Stoeckler. The authors are grateful to Dr. Joshua Baller, Research Informatics Scientific and Operations Lead with the Minnesota supercomputing Institute, for his bioinformatics assistance. We thank Michael J. Franklin, MS for editing the manuscript. All authors have read the journal’s authorship agreement and the policy on potential conflicts of interest.

Funding

This work is supported by a generous grant from the Mesothelioma Applied Research Foundation. Grant identification is: “Targeting cap-mediated translation for mesothelioma therapy”.

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Authors and Affiliations

  1. Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA

    Arpita De

  2. Department of Medicine, University of Minnesota, Minneapolis, MN, USA

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

  3. Division of Heme-Onc-Transplant, University of Minnesota Medical School, MMC 480, 420 Delaware St SE, Minneapolis, MN, 55455, USA

    Robert A. Kratzke

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  1. Arpita De
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De, A., Jacobson, B.A., Peterson, M.S. et al. 4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma. Invest New Drugs 36, 217–229 (2018). https://doi.org/10.1007/s10637-017-0535-z

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