4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma
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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.
Keywords4EGI-1 eIF4E eIF4G 4E–BP1 Cap-dependent translation Polysome Microarray
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.
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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Conflict of interest
All authors declare no potential conflicts of interest.
This article does not contain studies involving human participants or animals.
- 9.Crew JP, Fuggle S, Bicknell R, Cranston DW, de Benedetti A, Harris AL (2000) Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression. Br J Cancer 82(1):161–166CrossRefPubMedGoogle Scholar
- 28.Antman KH, Pass HI, Recht A (1989) Benign and malignant mesothelioma. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer: principle and practices of oncology, 3rd edn. J.B.Lippincot, Philadelphia, pp 1399–1417Google Scholar
- 36.Larsson O, Li S, Issaenko OA, Avdulov S, Peterson M, Smith K et al (2007) Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors. Cancer Res 67(14):6814–6824CrossRefPubMedGoogle Scholar
- 39.Larsson O, Perlman DM, Fan D, Reilly CS, Peterson M, Dahlgren C et al (2006) Apoptosis resistance downstream of eIF4E: posttranscriptional activation of an anti-apoptotic transcript carrying a consensus hairpin structure. Nucleic Acids ResGoogle Scholar
- 42.Sekiyama N, Arthanari H, Papadopoulos E, Rodriguez-Mias RA, Wagner G, Leger-Abraham M (2015) Molecular mechanism of the dual activity of 4EGI-1: dissociating eIF4G from eIF4E but stabilizing the binding of unphosphorylated 4E-BP1. Proc Natl Acad Sci U S A 112(30):E4036–E4045CrossRefPubMedPubMedCentralGoogle Scholar
- 50.Ito T, Tsukumo S, Suzuki N, Motohashi H, Yamamoto M, Fujii-Kuriyama Y et al (2004) A constitutively active arylhydrocarbon receptor induces growth inhibition of jurkat T cells through changes in the expression of genes related to apoptosis and cell cycle arrest. J Biol Chem 279(24):25204–25210CrossRefPubMedGoogle Scholar
- 52.Ouyang G, Yao L, Ruan K, Song G, Mao Y, Bao S (2009) Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways. Cell Biol IntGoogle Scholar
- 57.Li DQ, Wang L, Fei F, Hou YF, Luo JM, Zeng R et al (2006) Identification of breast cancer metastasis-associated proteins in an isogenic tumor metastasis model using two-dimensional gel electrophoresis and liquid chromatography-ion trap-mass spectrometry. Proteomics 6(11):3352–3368CrossRefPubMedGoogle Scholar