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 journalArticle

2 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)217-229
Number of pages13
JournalInvestigational New Drugs
Volume36
Issue number2
DOIs
StatePublished - Apr 1 2018

Fingerprint

Eukaryotic Initiation Factor-4F
Genome
gemcitabine
Pemetrexed
Osteopontin
Polyribosomes
Neoplasm Genes
Mesothelioma
Microarray Analysis
Genes
Cell Survival
Proteins
Breast
Epithelial Cells
Apoptosis
Malignant Mesothelioma

Keywords

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma. / De, Arpita; Jacobson, Blake A; Peterson, Mark S.; Jay-Dixon, Joe; Kratzke, Marian G.; Sadiq, Ahad A.; Patel, Manish R; Kratzke, Robert A.

In: Investigational New Drugs, Vol. 36, No. 2, 01.04.2018, p. 217-229.

Research output: Contribution to journalArticle

De, Arpita ; Jacobson, Blake A ; Peterson, Mark S. ; Jay-Dixon, Joe ; Kratzke, Marian G. ; Sadiq, Ahad A. ; Patel, Manish R ; Kratzke, Robert A. / 4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma. In: Investigational New Drugs. 2018 ; Vol. 36, No. 2. pp. 217-229.
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