Investigational New Drugs

, Volume 32, Issue 4, pp 598–603 | Cite as

Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells

  • Esther Z. Chen
  • Blake A. Jacobson
  • Manish R. Patel
  • Aniekan M. Okon
  • Shui Li
  • Kerry Xiong
  • Abhishek J. Vaidya
  • Peter B. Bitterman
  • Carston R. Wagner
  • Robert A. KratzkeEmail author


Deranged cap-mediated translation is implicated in the genesis, maintenance and progression of many human cancers including mesothelioma. In this study, disrupting the eIF4F complex by antagonizing the eIF4E-mRNA-cap interaction is assessed as a therapy for mesothelioma. Mesothelioma cells were treated with 4Ei-1, a membrane permeable prodrug that when converted to the active drug, 7-benzyl guanosine monophosphate (7Bn-GMP) displaces capped mRNAs from the eIF4F complex. Colony formation was measured in mesothelioma treated with 4Ei-1 alone or combined with pemetrexed. Proliferation was examined in cells treated with 4Ei-1. Binding to a synthetic cap-analogue was used to study the strength of eIF4F complex activation in lysates exposed to 4Ei-1. 4Ei-1 treatment resulted in a dose dependent decrease in colony formation and cell viability. Combination therapy of 4Ei-1 with pemetrexed further reduced colony number. Formation of eIF4F cap-complex decreased in response to 4Ei-1 exposure. 4Ei-1 is a novel prodrug that reduces proliferation, represses colony formation, diminishes association of eIF4F with the mRNA cap, and sensitizes mesothelioma cells to pemetrexed.


Mesothelioma eIF4E 4Ei-1 7-benzyl guanosine monophosphate Cap-dependent translation 



We would like to thank Sabine Darling, Nate Rietvold and Ryan McDonald for their technical assistance.

Disclosure of Potential Conflicts of Interest

All other authors declare no potential conflicts of interest.


  1. 1.
    Britton M (2002) The epidemiology of mesothelioma. Semin Oncol 29:18–25CrossRefPubMedGoogle Scholar
  2. 2.
    Carbone M, Albelda SM, Broaddus VC et al (2007) Eighth international mesothelioma interest group. Oncogene 26:6959–6967CrossRefPubMedGoogle Scholar
  3. 3.
    Hiremath LS, Webb NR, Rhoads RE (1985) Immunological detection of the messenger RNA cap-binding protein. J Biol Chem 260:7843–7849PubMedGoogle Scholar
  4. 4.
    Duncan R, Milburn SC, Hershey JW (1987) 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 262:380–388PubMedGoogle Scholar
  5. 5.
    Silvera D, Formenti SC, Schneider RJ (2010) Translational control in cancer. Nat Rev Cancer 10:254–266CrossRefPubMedGoogle Scholar
  6. 6.
    Thumma SC, Kratzke RA (2007) Translational control: a target for cancer therapy. Cancer Lett 258:1–8CrossRefPubMedGoogle Scholar
  7. 7.
    Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136:731–745PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Hsieh AC, Ruggero D (2010) Targeting eukaryotic translation initiation factor 4E (eIF4E) in cancer. Clin Cancer Res 16:4914–4920CrossRefPubMedGoogle Scholar
  9. 9.
    Polunovsky VA, Bitterman PB (2006) The cap-dependent translation apparatus integrates and amplifies cancer pathways. RNA Biol 3:10–17CrossRefPubMedGoogle Scholar
  10. 10.
    Lazaris-Karatzas A, Montine KS, Sonenberg N (1990) Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature 345:544–547CrossRefPubMedGoogle Scholar
  11. 11.
    Avdulov S, Li S, Michalek V et al (2004) Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 5:553–563CrossRefPubMedGoogle Scholar
  12. 12.
    Graff JR, Konicek BW, Lynch RL et al (2009) eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival. Cancer Res 69:3866–3873CrossRefPubMedGoogle Scholar
  13. 13.
    Jacobson BA, Alter MD, Kratzke MG et al (2006) Repression of cap-dependent translation attenuates the transformed phenotype in non-small cell lung cancer both in vitro and in vivo. Cancer Res 66:4256–4262CrossRefPubMedGoogle Scholar
  14. 14.
    Coleman LJ, Peter MB, Teall TJ et al (2009) Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity. Br J Cancer 100:1393–1399PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Chen CN, Hsieh FJ, Cheng YM, Lee PH, Chang KJ (2004) Expression of eukaryotic initiation factor 4E in gastric adenocarcinoma and its association with clinical outcome. J Surg Oncol 86:22–27CrossRefPubMedGoogle Scholar
  16. 16.
    Rosenwald IB, Chen JJ, Wang S, Savas L, London IM, Pullman J (1999) Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 18:2507–2517CrossRefPubMedGoogle Scholar
  17. 17.
    Salehi Z, Mashayekhi F, Shahosseini F (2007) Significance of eIF4E expression in skin squamous cell carcinoma. Cell Biol Int 31:1400–1404CrossRefPubMedGoogle Scholar
  18. 18.
    Wang S, Rosenwald IB, Hutzler MJ et al (1999) Expression of the eukaryotic translation initiation factors 4E and 2alpha in non-Hodgkin’s lymphomas. Am J Pathol 155:247–255PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Bauer C, Brass N, Diesinger I, Kayser K, Grasser FA, Meese E (2002) Overexpression of the eukaryotic translation initiation factor 4G (eIF4G-1) in squamous cell lung carcinoma. Int J Cancer 98:181–185CrossRefPubMedGoogle Scholar
  20. 20.
    Shuda M, Kondoh N, Tanaka K et al (2000) Enhanced expression of translation factor mRNAs in hepatocellular carcinoma. Anticancer Res 20:2489–2494PubMedGoogle Scholar
  21. 21.
    Patel MR, Jacobson BA, De A et al (2007) Ras pathway activation in malignant mesothelioma. J Thorac Oncol 2:789–795CrossRefPubMedGoogle Scholar
  22. 22.
    Jacobson BA, De A, Kratzke MG et al (2009) Activated 4E-BP1 represses tumourigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma. Br J Cancer 101:424–431PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Moerke NJ, Aktas H, Chen H et al (2007) Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 128:257–267CrossRefPubMedGoogle Scholar
  24. 24.
    Cencic R, Hall DR, Robert F et al (2010) Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F. Proc Natl Acad Sci U S A 108:1046–1051PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Herbert TP, Fahraeus R, Prescott A, Lane DP, Proud CG (2000) Rapid induction of apoptosis mediated by peptides that bind initiation factor eIF4E. Curr Biol 10:793–796CrossRefPubMedGoogle Scholar
  26. 26.
    Ko SY, Guo H, Barengo N, Naora H (2009) Inhibition of ovarian cancer growth by a tumor-targeting peptide that binds eukaryotic translation initiation factor 4E. Clin Cancer Res 15:4336–4347CrossRefPubMedGoogle Scholar
  27. 27.
    Graff JR, Konicek BW, Vincent TM et al (2007) Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. J Clin Invest 117:2638–2648PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    DeFatta RJ, Nathan CA, De Benedetti A (2000) Antisense RNA to eIF4E suppresses oncogenic properties of a head and neck squamous cell carcinoma cell line. Laryngoscope 110:928–933CrossRefPubMedGoogle Scholar
  29. 29.
    Soni A, Akcakanat A, Singh G et al (2008) eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling. Mol Cancer Ther 7:1782–1788PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Li S, Jia Y, Jacobson B et al (2013) Treatment of breast and lung cancer cells with a N-7 benzyl guanosine monophosphate tryptamine phosphoramidate pronucleotide (4Ei-1) results in chemosensitization to gemcitabine and induced eIF4E proteasomal degradation. Mol Pharm 10:523–531CrossRefPubMedGoogle Scholar
  31. 31.
    Jia Y, Chiu TL, Amin EA, Polunovsky V, Bitterman PB, Wagner CR (2010) Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn7-GMP. Eur J Med Chem 45:1304–1313PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Cencic R, Carrier M, Trnkus A, Porco JA Jr, Minden M, Pelletier J (2009) Synergistic effect of inhibiting translation initiation in combination with cytotoxic agents in acute myelogenous leukemia cells. Leuk Res 34:535–541PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Dong K, Wang R, Wang X et al (2009) Tumor-specific RNAi targeting eIF4E suppresses tumor growth, induces apoptosis and enhances cisplatin cytotoxicity in human breast carcinoma cells. Breast Cancer Res Treat 113:443–456CrossRefPubMedGoogle Scholar
  34. 34.
    Jacobson BA, Thumma SC, Jay-Dixon J et al (2013) Targeting eukaryotic translation in mesothelioma cells with an eIF4E-specific antisense oligonucleotide. PLoS One 8:e81669PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Bitterman PB, Polunovsky VA (2012) Attacking a nexus of the oncogenic circuitry by reversing aberrant eIF4F-mediated translation. Mol Cancer Ther 11:1051–1061PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Bitterman PB, Polunovsky VA (2012) Translational control of cell fate: from integration of environmental signals to breaching anticancer defense. Cell Cycle 11:1097–1107CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Esther Z. Chen
    • 1
  • Blake A. Jacobson
    • 1
  • Manish R. Patel
    • 1
  • Aniekan M. Okon
    • 2
  • Shui Li
    • 2
  • Kerry Xiong
    • 1
  • Abhishek J. Vaidya
    • 1
  • Peter B. Bitterman
    • 1
  • Carston R. Wagner
    • 2
  • Robert A. Kratzke
    • 1
    • 3
    Email author
  1. 1.Department of MedicineUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Medicinal ChemistryUniversity of MinnesotaMinneapolisUSA
  3. 3.Division of Hematology, Oncology and TransplantationUniversity of Minnesota Medical SchoolMinneapolisUSA

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