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

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

doi:10.1007/s10637-017-0535-z

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

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

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	217-229
Number of pages	13
Journal	Investigational New Drugs
Volume	36
Issue number	2
DOIs	https://doi.org/10.1007/s10637-017-0535-z
State	Published - Apr 1 2018

Bibliographical note

Funding Information:
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 Information:
Funding This work is supported by a generous grant from the Mesothelioma Applied Research Foundation. Grant identification is: BTargeting cap-mediated translation for mesothelioma therapy^.

Publisher Copyright:
© 2017, Springer Science+Business Media, LLC.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

4EGI-1
4E–BP1
Cap-dependent translation
Microarray
Polysome
eIF4E
eIF4G

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s10637-017-0535-z

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title = "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.",

keywords = "4EGI-1, 4E–BP1, Cap-dependent translation, Microarray, Polysome, eIF4E, eIF4G",

author = "Arpita De and Jacobson, {Blake A.} and Peterson, {Mark S.} and Joe Jay-Dixon and Kratzke, {Marian G.} and Sadiq, {Ahad A.} and Patel, {Manish R.} and Kratzke, {Robert A.}",

note = "Funding Information: 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{\textquoteright}s authorship agreement and the policy on potential conflicts of interest. Funding Information: Funding This work is supported by a generous grant from the Mesothelioma Applied Research Foundation. Grant identification is: BTargeting cap-mediated translation for mesothelioma therapy^. Publisher Copyright: {\textcopyright} 2017, Springer Science+Business Media, LLC. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2018",

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doi = "10.1007/s10637-017-0535-z",

language = "English (US)",

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AU - De, Arpita

AU - Jacobson, Blake A.

AU - Peterson, Mark S.

AU - Jay-Dixon, Joe

AU - Kratzke, Marian G.

AU - Sadiq, Ahad A.

AU - Patel, Manish R.

AU - Kratzke, Robert A.

N1 - Funding Information: 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 Information: Funding This work is supported by a generous grant from the Mesothelioma Applied Research Foundation. Grant identification is: BTargeting cap-mediated translation for mesothelioma therapy^. Publisher Copyright: © 2017, Springer Science+Business Media, LLC. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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