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

Our plain-English summary of 4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma, by A. De, B.A. Jacobson, M.S. Peterson, et al (Investigational New Drugs, 2018).

The study

• Authors: A. De, B.A. Jacobson, M.S. Peterson, J. Jay-Dixon, M.G. Kratzke, A.A. Sadiq, M.R. Patel, R.A. Kratzke
• Journal: Investigational New Drugs
• Published: 2018;36(2):217-229
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This was a laboratory study of human cells grown in dishes. It involved no patients or animals and did not study asbestos exposure. The authors tested 4EGI-1, an experimental compound that blocks a step cells use to start making proteins, on malignant pleural mesothelioma cell lines and on normal mesothelial cells (LP9). The compound strongly reduced the number of living cells in two mesothelioma lines at 25 or 50 micromolar, with a relatively modest effect on the normal cells. It increased a marker of apoptosis (programmed cell death) in mesothelioma cells but not in normal cells. At 100 micromolar, the proteins c-myc and osteopontin fell to 25% and 41% of untreated levels in H2596 cells, and to 44% and 74% in H2461 cells. Neither protein fell in normal cells. Combining 4EGI-1 with pemetrexed or gemcitabine gave a cooperative effect. A genome-wide analysis found the drug's effects on protein-making ran strongly opposite to those of eIF4E overexpression in breast cells from an earlier study. The authors concluded this approach could be a strategy for treating mesothelioma. They also noted 4EGI-1 itself may not be potent enough for clinical use.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) cell-line study; the article states it involved no human participants or animals
• Who was studied: Human malignant pleural mesothelioma cell lines H2596, H2461 and H2373 (from the American Type Culture Collection), and non-transformed human mesothelial cells (LP9); work done at the University of Minnesota
• Exposure: The experimental translation inhibitor 4EGI-1 (concentrations up to 100 or 200 micromolar depending on experiment), alone and combined with pemetrexed or gemcitabine; no asbestos or fiber exposure was studied
• Main results:
  • 4EGI-1 strongly reduced viability of mesothelioma cells H2596 and H2461 at 25 or 50 micromolar, with a relatively modest effect on normal LP9 cells
  • A marker of apoptosis (cleaved PARP) increased with dose in mesothelioma cells but not in LP9 cells
  • In H2596 cells at 100 micromolar, c-myc fell to 25% and osteopontin to 41% of untreated levels
  • In H2461 cells, c-myc fell to 44% and osteopontin to 74% of untreated levels
  • c-myc and osteopontin did not decrease in normal LP9 cells
  • The active (hypophosphorylated) form of 4E-BP1 rose with dose in both mesothelioma cell lines, while in LP9 cells it stayed nearly constant (52.1 to 64.8%)
  • 4EGI-1 combined with pemetrexed or gemcitabine gave a cooperative effect compared with either chemotherapy drug alone
  • Genome-wide translation changes in 4EGI-1-treated H2596 cells were negatively correlated with changes from eIF4E overexpression in previously published human mammary epithelial cell data. The authors called this a highly significant anti-correlation, p less than 10e−15 as printed
• The authors' conclusion: The authors concluded that inhibiting the eIF4F complex with 4EGI-1 or similar translation inhibitors could be a strategy for treating mesothelioma
• Limitations the authors state:
  • 4EGI-1 may not be potent enough for clinical use
  • An increase in bound eIF4E in the cap-binding assays could not be explained
  • Further work is needed to explain the drug's effect on 4E-BP1 phosphorylation

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Malignant Transformation, Apoptosis, Osteopontin, Pemetrexed (Alimta), Gemcitabine, Polysome, Mesothelioma.

Related studies

• Novel role of c-jun N-terminal kinase in regulating the initiation of cap-dependent translation — M.R. Patel, A.A. Sadiq, et al. (2012)
• Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells — E.Z. Chen, B.A. Jacobson, et al. (2014)
• Sensitivity of global translation to mTOR inhibition in REN cells depends on the equilibrium between eIF4E and 4E-BP1 — S. Grosso, E. Pesce, et al. (2011)
• Repression of oncogenic cap-mediated translation by 4Ei-10 diminishes proliferation, enhances chemosensitivity and alters expression of malignancy-related proteins in mesothelioma — Z. Ahmad, B.A. Jacobson, et al. (2020)
• Establishment and mutation analysis of a novel malignant peritoneal mesothelioma cell line, TU-MM-1, using whole genome sequencing — N. Oumi, H. Itamochi, et al. (2016)
• Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma — M.L. Hartman, J.M. Esposito, et al. (2010)

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