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Repression of oncogenic cap-mediated translation by 4Ei-10 diminishes proliferation, enhances chemosensitivity and alters expression of malignancy-related proteins in mesothelioma

Abstract

Activated cap-dependent translation promotes cancer by stimulating translation of mRNAs encoding malignancy-promoting proteins. The nucleoside monophosphate Protide, 4Ei-10, undergoes intracellular uptake and conversion by Hint1 to form 7-Cl-Ph-Ethyl-GMP. 7-Cl-Ph-Ethyl-GMP is an analog of cap and inhibits protein translation by binding and sequestering eIF4E thus blocking eIF4E from binding to the mRNA cap. The effects of inhibiting translation initiation by disruption of the eIF4F complex with 4Ei-10 were examined in malignant mesothelioma (MM). In a cell-free assay system, formation of the eIF4F complex was disabled in response to exposure to 4Ei-10. Treatment of MM with 4Ei-10 resulted in decreased cell proliferation, increased sensitivity to pemetrexed and altered expression of malignancy-related proteins. In light of these findings, suppression of translation initiation by small molecule inhibitors like 4Ei-10 alone or in combination with pemetrexed represents an encouraging strategy meriting further evaluation in the treatment of MM.

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Acknowledgements

This work was supported in part by the Harvey Carlson Mesothelioma Research Fund. All authors have read the journal's authorship agreement and the policy on potential conflicts of interest.

Funding

This work was funded in part by the Harvey Carlson Mesothelioma Research Fund of the University of Minnesota.

Author information

Conceived and designed the experiments: Z.A., B.A.J, M.R.P., C.R.W., R.A.K. Performed the experiments: Z.A., B.A.J, M.W.M., N.V.V., G.V.V., S.C. Analyzed the data: Z.A., B.A.J, M.W.M., N.V.V., G.V.V., S.C., M.D., A.M.O., M.R.P., C.R.W., R.A.K. Contributed reagents/materials/analytic tools: M.D., A.M.O., M.R.P., C.R.W., R.A.K. Wrote the main manuscript: Z.A., B.A.J, R.A.K. Wrote subsequent drafts of manuscript: Z.A., B.A.J, M.D., M.R.P., C.R.W., R.A.K. Reviewed and approved the final version of the manuscript: Z.A., B.A.J, M.W.M., N.V.V., G.V.V., S.C., M.D., A.M.O., M.R.P., C.R.W., R.A.K.

Correspondence to Robert A. Kratzke.

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Conflict of interest

Author Zeeshan Ahmad has no conflict of interest, author Blake A. Jacobson has no conflict of interest, author Mitchell W. McDonald has no conflict of interest, author Nicolas Vattendahl Vidal has no conflict of interest, author Gabriel Vattendahl Vidal has no conflict of interest, author Sierra Chen has no conflict of interest, author Maxwell Dillenburg has no conflict of interest, author Aniekan M. Okon has no conflict of interest, author Manish R. Patel has no conflict of interest, author Carston R. Wagner has no conflict of interest, and author Robert A. Kratzke has no conflict of interest.

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Ahmad, Z., Jacobson, B.A., McDonald, M.W. et al. Repression of oncogenic cap-mediated translation by 4Ei-10 diminishes proliferation, enhances chemosensitivity and alters expression of malignancy-related proteins in mesothelioma. Cancer Chemother Pharmacol 85, 425–432 (2020). https://doi.org/10.1007/s00280-020-04029-9

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Keywords

  • Mesothelioma
  • 4Ei-10
  • ProTide
  • eIF4E
  • eIF4G
  • Cap-dependent translation
  • 7-Cl-Ph-Ethyl-GMP