Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Inhibition of oncogenic cap-dependent translation by 4EGI-1 reduces growth, enhances chemosensitivity and alters genome-wide translation in non-small cell lung cancer

Cancer Gene Therapy volume 26, pages 157–165 (2019)Cite this article

Subjects

Abstract

Hyperactivation of eIF4F-mediated translation occurs in many if not all cancers. As a consequence, cancer cells aberrantly enhance expression of malignancy-related proteins that are involved in cell cycle progression, angiogenesis, growth, and proliferation. With this in mind eIF4F is a promising molecular target for therapeutics that counteract pathological eIF4F activity. Here we used 4EGI-1, a small-molecule inhibitor of cap-mediated translation that disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex to treat non-small cell lung cancer (NSCLC). Treatment of cells with 4EGI-1 reduced cell proliferation, decreased cap-dependent complex formation, induced apoptosis, enhanced sensitivity to gemcitabine, and altered global cellular translation. Suppression of cap-dependent translation by 4EGI-1 resulted in diminished expression of oncogenic proteins c-Myc, Bcl-2, cyclin D1, and survivin, whereas β-actin expression was left unchanged. In light of these results, small-molecule inhibitors like 4EGI-1 alone or with chemotherapy should be further evaluated in the treatment of NSCLC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.

    PubMed  Google Scholar 

  2. Silvera D, Formenti SC, Schneider RJ. Translational control in cancer. Nat Rev Cancer. 2010;10:254–66.

    CAS  PubMed  Google Scholar 

  3. Jacobson BA, Alter MD, Kratzke MG, Frizelle SP, Zhang Y, Peterson MS, et al. Repression of cap-dependent translation attenuates the transformed phenotype in non-small cell lung cancer both in vitro and in vivo. Cancer Res. 2006;66:4256–62.

    CAS  PubMed  Google Scholar 

  4. Hiremath LS, Webb NR, Rhoads RE. Immunological detection of the messenger RNA cap-binding protein. J Biol Chem. 1985;260:7843–9.

    CAS  PubMed  Google Scholar 

  5. Duncan R, Milburn SC, Hershey JW. Regulated phosphorylation and low abundance of HeLa cell initiation factor eIF-4F suggest a role in translational control. Heat shock effects on eIF-4F. J Biol Chem. 1987;262:380–8.

    CAS  PubMed  Google Scholar 

  6. Thumma SC, Kratzke RA. Translational control: a target for cancer therapy. Cancer Lett. 2007;258:1–8.

    CAS  PubMed  Google Scholar 

  7. Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell. 2009;136:731–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hsieh AC, Ruggero D. Targeting eukaryotic translation initiation factor 4E (eIF4E) in cancer. Clin Cancer Res. 2010;16:4914–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Polunovsky VA, Bitterman PB. The cap-dependent translation apparatus integrates and amplifies cancer pathways. RNA Biol. 2006;3:10–7.

    CAS  PubMed  Google Scholar 

  10. Coleman LJ, Peter MB, Teall TJ, Brannan RA, Hanby AM, Honarpisheh H, et al. Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity. Br J Cancer. 2009;100:1393–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Graff JR, Konicek BW, Lynch RL, Dumstorf CA, Dowless MS, McNulty AM, et al. eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival. Cancer Res. 2009;69:3866–73.

    CAS  PubMed  Google Scholar 

  12. Chen CN, Hsieh FJ, Cheng YM, Lee PH, Chang KJ. Expression of eukaryotic initiation factor 4E in gastric adenocarcinoma and its association with clinical outcome. J Surg Oncol. 2004;86:22–7.

    CAS  PubMed  Google Scholar 

  13. Rosenwald IB, Chen JJ, Wang S, Savas L, London IM, Pullman J. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene. 1999;18:2507–17.

    CAS  PubMed  Google Scholar 

  14. Salehi Z, Mashayekhi F, Shahosseini F. Significance of eIF4E expression in skin squamous cell carcinoma. Cell Biol Int. 2007;31:1400–4.

    CAS  PubMed  Google Scholar 

  15. Bauer C, Brass N, Diesinger I, Kayser K, Grasser FA, Meese E. Overexpression of the eukaryotic translation initiation factor 4G (eIF4G-1) in squamous cell lung carcinoma. Int J Cancer. 2002;98:181–5.

    CAS  PubMed  Google Scholar 

  16. Shuda M, Kondoh N, Tanaka K, Ryo A, Wakatsuki T, Hada A, et al. Enhanced expression of translation factor mRNAs in hepatocellular carcinoma. Anticancer Res. 2000;20:2489–94.

    CAS  PubMed  Google Scholar 

  17. Chen EZ, Jacobson BA, Patel MR, Okon AM, Li S, Xiong K, et al. Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells. Invest New Drugs. 2014;32:598–603.

    CAS  PubMed  Google Scholar 

  18. Okon A, Han J, Dawadi S, Demosthenous C, Aldrich CC, Gupta M, et al. Anchimerically activated ProTides as inhibitors of cap-dependent translation and inducers of chemosensitization in mantle cell lymphoma. J Med Chem. 2017;60:8131–44.

    CAS  PubMed  Google Scholar 

  19. Graff JR, Konicek BW, Vincent TM, Lynch RL, Monteith D, Weir SN, et al. Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. J Clin Invest. 2007;117:2638–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Thumma SC, Jacobson BA, Patel MR, Konicek BW, Franklin MJ, Jay-Dixon J, et al. Antisense oligonucleotide targeting eukaryotic translation initiation factor 4E reduces growth and enhances chemosensitivity of non-small-cell lung cancer cells. Cancer Gene Ther. 2015;22:396–401.

    CAS  PubMed  Google Scholar 

  21. DeFatta RJ, Nathan CA, De Benedetti A. Antisense RNA to eIF4E suppresses oncogenic properties of a head and neck squamous cell carcinoma cell line. Laryngoscope. 2000;110:928–33.

    CAS  PubMed  Google Scholar 

  22. Herbert TP, Fahraeus R, Prescott A, Lane DP, Proud CG. Rapid induction of apoptosis mediated by peptides that bind initiation factor eIF4E. Curr Biol. 2000;10:793–6.

    CAS  PubMed  Google Scholar 

  23. Ko SY, Guo H, Barengo N, Naora H. Inhibition of ovarian cancer growth by a tumor-targeting peptide that binds eukaryotic translation initiation factor 4E. Clin Cancer Res. 2009;15:4336–47.

    CAS  PubMed  Google Scholar 

  24. Avdulov S, Li S, Michalek V, Burrichter D, Peterson M, Perlman DM, et al. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell. 2004;5:553–63.

    CAS  PubMed  Google Scholar 

  25. Moerke NJ, Aktas H, Chen H, Cantel S, Reibarkh MY, Fahmy A, et al. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell. 2007;128:257–67.

    CAS  PubMed  Google Scholar 

  26. Cencic R, Hall DR, Robert F, Du Y, Min J, Li L, et al. Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F. Proc Natl Acad Sci USA. 2010;108:1046–51.

    PubMed  PubMed Central  Google Scholar 

  27. Sekiyama N, Arthanari H, Papadopoulos E, Rodriguez-Mias RA, Wagner G, Leger-Abraham M. 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 USA. 2015;112:E4036–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen L, Aktas BH, Wang Y, He X, Sahoo R, Zhang N, et al. Tumor suppression by small molecule inhibitors of translation initiation. Oncotarget. 2012;3:869–81.

    PubMed  PubMed Central  Google Scholar 

  29. Wu M, Zhang C, Li XJ, Liu Q, Wanggou S. Anti-cancer effect of cap-translation inhibitor 4EGI-1 in human glioma U87 cells: involvement of mitochondrial dysfunction and ER stress. Cell Physiol Biochem. 2016;40:1013–28.

    CAS  PubMed  Google Scholar 

  30. Descamps G, Gomez-Bougie P, Tamburini J, Green A, Bouscary D, Maiga S, et al. The cap-translation inhibitor 4EGI-1 induces apoptosis in multiple myeloma through Noxa induction. Br J Cancer. 2012;106:1660–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Willimott S, Beck D, Ahearne MJ, Adams VC, Wagner SD. Cap-translation inhibitor, 4EGI-1, restores sensitivity to ABT-737 apoptosis through cap-dependent and -independent mechanisms in chronic lymphocytic leukemia. Clin Cancer Res. 2013;19:3212–23.

    CAS  PubMed  Google Scholar 

  32. Schwarzer A, Holtmann H, Brugman M, Meyer J, Schauerte C, Zuber J, et al. Hyperactivation of mTORC1 and mTORC2 by multiple oncogenic events causes addiction to eIF4E-dependent mRNA translation in T-cell leukemia. Oncogene. 2015;34:3593–604.

    CAS  PubMed  Google Scholar 

  33. De A, Jacobson BA, Peterson MS, Jay-Dixon J, Kratzke MG, Sadiq AA, et al. 4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma. Invest New Drugs. 2018;36:217–29.

    CAS  PubMed  Google Scholar 

  34. Fan S, Li Y, Yue P, Khuri FR, Sun SY. The eIF4E/eIF4G interaction inhibitor 4EGI-1 augments TRAIL-mediated apoptosis through c-FLIP down-regulation and DR5 induction independent of inhibition of cap-dependent protein translation. Neoplasia. 2010;12:346–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Jacobson BADA, Kratzke MG, Patel MR, Jay DixonJ, Whitson BA, Sadiq AA, et al. Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma. Br J Cancer. 2009;101:424–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Li S, Takasu T, Perlman DM, Peterson MS, Burrichter D, Avdulov S, et al. Translation factor eIF4E rescues cells from Myc-dependent apoptosis by inhibiting cytochrome c release. J Biol Chem. 2003;278:3015–22.

    CAS  PubMed  Google Scholar 

  37. Bitterman PB, Polunovsky VA. Attacking a nexus of the oncogenic circuitry by reversing aberrant eIF4F-mediated translation. Mol Cancer Ther. 2012;11:1051–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, et al. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev. 2001;15:2852–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zimmer SG, DeBenedetti A, Graff JR. Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis. Anticancer Res. 2000;20(3A):1343–51.

    CAS  PubMed  Google Scholar 

  40. Coudert L, Adjibade P, Mazroui R. Analysis of translation initiation during stress conditions by polysome profiling. J Vis Exp. 2014; 87;1–7.

  41. Malina A, Cencic R, Pelletier J. Targeting translation dependence in cancer. Oncotarget. 2011;2:76–88.

    PubMed  PubMed Central  Google Scholar 

  42. Guo S, Martin MG, Tian C, Cui J, Wang L, Wu S, et al. Evaluation of detection methods and values of circulating vascular endothelial growth factor in lung cancer. J Cancer. 2018;9:1287–300.

    PubMed  PubMed Central  Google Scholar 

  43. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378:2288–301.

    CAS  PubMed  Google Scholar 

  44. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078–92.

    CAS  PubMed  Google Scholar 

  45. Yoshizawa A, Fukuoka J, Shimizu S, Shilo K, Franks TJ, Hewitt SM, et al. Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. Clin Cancer Res. 2010;16:240–8.

    CAS  PubMed  Google Scholar 

  46. Fan S, Ramalingam SS, Kauh J, Xu Z, Khuri FR, Sun SY. Phosphorylated eukaryotic translation initiation factor 4 (eIF4E) is elevated in human cancer tissues. Cancer Biol Ther. 2009;8:1463–9.

    PubMed  Google Scholar 

  47. Lin CJ, Malina A, Pelletier J. c-Myc and eIF4F constitute a feedforward loop that regulates cell growth: implications for anticancer therapy. Cancer Res. 2009;69:7491–4.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

All authors have read the journal’s authorship agreement and the policy on potential conflicts of interest. Funding that supported this work was the John Skoglund Lung Cancer Research Endowment.

Author information

Authors and Affiliations

  1. University of Minnesota, Department of Pharmacology, Minneapolis, MN, USA

    Arpita De

  2. University of Minnesota, Department of Medicine, Minneapolis, MN, USA

    Blake A. Jacobson, Mark S. Peterson, Margaret E. Stelzner, Joe Jay-Dixon, Marian G. Kratzke, Manish R. Patel, Peter B. Bitterman & Robert A. Kratzke

Authors
  1. Arpita De
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Blake A. Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark S. Peterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margaret E. Stelzner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joe Jay-Dixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marian G. Kratzke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Manish R. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter B. Bitterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Robert A. Kratzke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert A. Kratzke.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain studies involving human participants or animals.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

De, A., Jacobson, B.A., Peterson, M.S. et al. Inhibition of oncogenic cap-dependent translation by 4EGI-1 reduces growth, enhances chemosensitivity and alters genome-wide translation in non-small cell lung cancer. Cancer Gene Ther 26, 157–165 (2019). https://doi.org/10.1038/s41417-018-0058-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-018-0058-6

This article is cited by

Search

Advanced search

Quick links