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.

  • Review Article
  • Published:

The biological and therapeutic relevance of mRNA translation in cancer

Nature Reviews Clinical Oncology volume 8, pages 280–291 (2011)Cite this article

Subjects

Abstract

Protein synthesis is a tightly regulated process that enables post-transcriptional control of gene expression. Dysregulation of this process is associated with the development and progression of cancers because components of the translational machinery function at the point of convergence of aberrant cell signaling pathways. Drugs designed to inhibit mRNA translation are currently in preclinical and early clinical development, and are likely to provide effective anticancer strategies in the future. In this Review, we summarize the main components of translation and describe how alterations in these proteins and their principle upstream signaling pathways can impact on cancer. The first inhibitors of translation, drugs designed to target eIF4E, have been trialed in hematologic malignancies, while antisense oligonucleotides against eIF4E are also due to enter clinical trials. Here, we discuss the mode of action of drugs designed to inhibit mRNA translation and other promising therapies that are in preclinical development with the aim of becoming anticancer agents.

Key Points

  • The initiation of mRNA translation is regulated by the PI3K and MAPK pathways

  • Protein components of the translational machinery have been shown to be amplified or overexpressed in malignancies, and can be oncogenic

  • Drugs targeting proteins involved in translation have shown anticancer activity in preclinical and early clinical trials

  • Agents rationally designed to target translation have the potential to be used alone or together with cytotoxic chemotherapy to increase apoptosis and overcome resistance to chemotherapy

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

Figure 1: The 48S preinitiation complex.
Figure 2: The principle cell signaling pathways that converge on mRNA translation initiation and their inhibitors.

Similar content being viewed by others

References

  1. Brenner, S., Jacob, F. & Meselson, M. An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature 1 90, 576–581 (1961).

    Article  Google Scholar 

  2. Spiegelman, S. The relation of informational RNA to DNA. Cold Spring Harb. Symp. Quant. Biol. 26, 75–90 (1961).

    Article  CAS  PubMed  Google Scholar 

  3. Jacob, F. & Monod, J. Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3, 318–356 (1961).

    Article  CAS  PubMed  Google Scholar 

  4. Gingras, A. C., Raught, B. & Sonenberg, N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68, 913–963 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Merrick, W. C. & Hershey, J. W. B. in Translational control Vol. 30 Ch. 2 (eds Hershey, J. W. B., Mathews, M. B. & Sonenberg, N.) 31–70 (Cold Spring Harbor Laboratory Press, New York, 1996).

    Google Scholar 

  6. Deo, R. C., Bonanno, J. B., Sonenberg, N. & Burley, S. K. Recognition of polyadenylate RNA by the poly(A)-binding protein. Cell 98, 835–845 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Imataka, H., Gradi, A. & Sonenberg, N. A newly identified N-terminal amino acid sequence of human eIF4G binds poly(A)-binding protein and functions in poly(A)-dependent translation. EMBO J. 17, 7480–7489 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wells, S. E., Hillner, P. E., Vale, R. D. & Sachs, A. B. Circularization of mRNA by eukaryotic translation initiation factors. Mol. Cell 2, 135–140 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Bushell, M. et al. Disruption of the interaction of mammalian protein synthesis eukaryotic initiation factor 4B with the poly(A)-binding protein by caspase- and viral protease-mediated cleavages. J. Biol. Chem. 276, 23922–23928 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Jackson, R. J., Hellen, C. U. & Pestova, T. V. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol. 11, 113–127 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jang, S. K. & Wimmer, E. Cap-independent translation of encephalomyocarditis virus RNA: structural elements of the internal ribosomal entry site and involvement of a cellular 57-kD RNA-binding protein. Genes Dev. 4, 1560–1572 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. Spriggs, K. A., Stoneley, M., Bushell, M. & Willis, A. E. Re-programming of translation following cell stress allows IRES-mediated translation to predominate. Biol. Cell 100, 27–38 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Mitchell, S. A., Spriggs, K. A., Coldwell, M. J., Jackson, R. J. & Willis, A. E. The Apaf-1 internal ribosome entry segment attains the correct structural conformation for function via interactions with PTB and unr. Mol. Cell 11, 757–771 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Pickering, B. M. & Willis, A. E. The implications of structured 5′ untranslated regions on translation and disease. Semin. Cell Dev. Biol. 16, 39–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Mitchell, S. A. et al. Identification of a motif that mediates polypyrimidine tract-binding protein-dependent internal ribosome entry. Genes Dev. 19, 1556–1571 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Spriggs, K. A. et al. Canonical initiation factor requirements of the Myc family of internal ribosome entry segments. Mol. Cell. Biol. 29, 1565–1574 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Marom, L. et al. Diverse poly(A) binding proteins mediate internal translational initiation by a plant viral IRES. RNA Biol. 6, 446–454 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Pause, A. et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function, Nature 371, 762–767 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Sonenberg, N. & Dever, T. E. Eukaryotic translation initiation factors and regulators. Curr. Opin. Struct. Biol. 13, 56–63 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell. 6, 1099–1108 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Dang Do, A. N., Kimball, S. R., Cavener, D. R. & Jefferson, L. S. eIF2α kinases GCN2 and PERK modulate transcription and translation of distinct sets of mRNAs in mouse liver. Physiol. Genomics 38, 328–341 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Beretta, L., Gingras, A. C., Svitkin, Y. V., Hall, M. N. & Sonenberg, N. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initation of translation. EMBO J. 15, 658–664 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gingras, A. C., Kennedy, S. G., O'Leary, M. A., Sonenberg, N. & Hay, N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev. 12, 502–513 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Holz, M. K., Ballif, B. A., Gygi, S. P. & Blenis, J. mTOR and S6K1 mediate assembly of the translation preinitation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123, 569–580 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Shahbazian, D. et al. The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J. 25, 2781–2791 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Scheper, G. C. & Proud, C. G. Does phosphorylation of the cap-binding protein eIF4E play a role in translation initiation? Eur. J. Biochem. 269, 5350–5359 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gelinas, J. N. et al. ERK and mTOR signaling couple beta-adrenergic receptors to translation initiation machinery to gate induction of protein synthesis-dependent long-term potentiation. J. Biol. Chem. 282, 27527–27535 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. She, Q. B. et al. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell 18, 39–51 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sarkar, S. N., Smith, L. T., Logan, S. M. & Simpkins, J. W. Estrogen-induced activation of extracellular signal-regulated kinase signaling triggers dendritic resident mRNA translation. Neuroscience 170, 1080–1085 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Kelleher, R. J. 3rd et al. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467–479 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Lazaris-Karatzas, A., Montine, K. S. & Sonenberg, N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature 345, 544–547 (1990).

    Article  CAS  PubMed  Google Scholar 

  32. De Benedetti, A. & Rhoads, R. E. Overexpression of eukaryotic protein synthesis initiation factor 4E in HeLa cells results in aberrant growth and morphology. Proc. Natl Acad. Sci. USA 87, 8212–8216 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. O'Reilly, K. E. et al. Phosphorylated 4E-BP1 is associated with poor survival in melanoma. Clin. Cancer Res. 15, 2872–2878 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Barnhart, B. C. et al. Effects of 4E-BP1 expression on hypoxic cell cycle inhibition and tumor cell proliferation and survival. Cancer Biol. Ther. 7, 1441–1449 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Zimmer, S. G., DeBenedetti, A. & Graff, J. R. Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis. Anticancer Res. 20, 1343–1351 (2000).

    CAS  PubMed  Google Scholar 

  36. Rhoads, R. E., Joshi-Barve, S. & Rinker-Schaeffer, C. Mechanism of action and regulation of protein synthesis initiation factor 4E: effects on mRNA discrimination, cellular growth rate, and oncogenesis. Prog. Nucleic Acid Res. Mol. Biol. 46, 183–219 (1993).

    Article  CAS  PubMed  Google Scholar 

  37. Graff, J. R. & Zimmer, S. G. Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs. Clin. Exp. Metastasis 20, 265–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. DeFatta, R. J., Turbat-Herrera, E. A., Li, B. D., Anderson, W. & De Benedetti, A. Elevated expression of eIF4E in confined early breast cancer lesions: possible role of hypoxia. Int. J. Cancer 80, 516–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Nathan, C. O. et al. Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/mammalian target of rapamycin pathway. Clin. Cancer Res. 10, 5820–5827 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Crew, J. P. et al. 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, 161–166 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Berkel, H. J., Turbat-Herrera, E. A., Shi, R. & de Benedetti, A. Expression of the translation initiation factor eIF4E in the polyp-cancer sequence in the colon. Cancer Epidemiol. Biomarkers Prev. 10, 663–666 (2001).

    CAS  PubMed  Google Scholar 

  42. Matthews-Greer, J. et al. eIF4E as a marker for cervical neoplasia. Appl. Immunohistochem. Mol. Morphol. 13, 367–370 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Wang, R. et al. Overexpression of eukaryotic initiation factor 4E (eIF4E) and its clinical significance in lung adenocarcinoma. Lung Cancer 66, 237–244 (2009).

    Article  PubMed  Google Scholar 

  44. Graff, J. R. et al. eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival. Cancer Res. 69, 3866–3873 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Yang, S. X., Hewitt, S. M., Steinberg, S. M., Liewehr, D. J. & Swain, S. M. Expression levels of eIF4E, VEGF, and cyclin D1, and correlation of eIF4E with VEGF and cyclin D1 in multi-tumor tissue microarray. Oncol. Rep. 17, 281–287 (2007).

    CAS  PubMed  Google Scholar 

  46. Ruszczy´nska-Bartnik, K., Maciejczyk, M. & Stolarski, R. Dynamical insight into Caenorhabditis elegans eIF4E recognition specificity for mono-and trimethylated structures of mRNA 5′ cap. J. Mol. Model. doi: 10.1007/s00894-010-0773-x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Rhoads, R. E. eIF4E: new family members, new binding partners, new roles. J. Biol. Chem. 284, 16711–16715 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gao, M., Rychlik, W. & Rhoads, R. E. Cloning and characterization of human eIF4E genes. J. Biol. Chem. 273, 4622–4628 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Rogers, G. W. Jr, Richter, N. J. & Merrick, W. C. Biochemical and kinetic characterization of the RNA helicase activity of eukaryotic initiation factor 4A. J. Biol. Chem. 274, 12236–12244 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Rogers, G. W. Jr, Richter, N. J., Lima, W. F. & Merrick, W. C. Modulation of the helicase activity of eIF4A by eIF4B, eIF4H, and eIF4F. J. Biol. Chem. 276, 30914–30922 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. LaRonde-LeBlanc, N., Santhanam, A. N., Baker, A. R., Wlodawer, A. & Colburn, N. H. Structural basis for inhibition of translation by the tumor suppressor Pdcd4. Mol. Cell Biol. 27, 147–156 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Jansen, A. P., Camalier, C. E., Stark, C. & Colburn, N. H. Characterization of programmed cell death 4 in multiple human cancers reveals a novel enhancer of drug sensitivity. Mol. Cancer Ther. 3, 103–110 (2004).

    CAS  PubMed  Google Scholar 

  53. Darveau, A., Pelletier, J. & Sonenberg, N. Differential efficiencies of in vitro translation of mouse c-myc transcripts differing in the 5′ untranslated region. Proc. Natl Acad. Sci. USA 82, 2315–2319 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shuda, M. et al. Enhanced expression of translation factor mRNAs in hepatocellular carcinoma. Anticancer Res. 20, 2489–2494 (2000).

    CAS  PubMed  Google Scholar 

  55. Eberle, J., Krasagakis, K. & Orfanos, C. E. Translation initiation factor eIF-4A1 mRNA is consistently overexpressed in human melanoma cells in vitro. Int. J. Cancer 71, 396–401 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Fukuchi-Shimogori, T. et al. Malignant transformation by overproduction of translation initiation factor eIF4G. Cancer Res. 57, 5041–5044 (1997).

    CAS  PubMed  Google Scholar 

  57. Braunstein, S. et al. A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. Mol. Cell. 28, 501–512 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Rojo, F. et al. 4E-binding protein 1, a cell signaling hallmark in breast cancer that correlates with pathologic grade and prognosis. Clin. Cancer Res. 1 3, 81–89 (2007).

    Article  Google Scholar 

  59. Comtesse, N. et al. Frequent overexpression of the genes FXR1, CLAPM1 and EIF4G located on amplicon 3q26–27 in squamous cell carcinoma of the lung. Int. J. Cancer 120, 2538–2544 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Bauer, C. et al. Translation initiation factor eIF-4G is immunogenic, overexpressed, and amplified in patients with squamous cell lung carcinoma. Cancer 92, 822–829 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Peterson, T. R. & Sabatini, D. M. eIF3: a connecTOR of S6K1 to the translation preinitiation complex. Mol. Cell. 20, 655–657 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Zhang, L., Pan, X. & Hershey, J. W. Individual overexpression of five subunits of human translation initiation factor eIF3 promotes malignant transformation of immortal fibroblast cells. J. Biol. Chem. 282, 5790–5800 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Haybaeck, J. et al. Overexpression of p150, a part of the large subunit of the eukaryotic translation initiation factor 3, in colon cancer. Anticancer Res. 30, 1047–1055 (2010).

    CAS  PubMed  Google Scholar 

  64. Chen, G. & Burger, M. M. p150 overexpression in gastric carcinoma: the association with p53, apoptosis and cell proliferation. Int. J. Cancer 112, 393–398 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Holcík, M. Targeting translation for treatment of cancer—a novel role for IRES? Curr. Cancer Drug Targets 4, 299–311 (2004).

    Article  PubMed  Google Scholar 

  66. van der Velden, A. W. & Thomas, A. A. The role of the 5′ untranslated region of an mRNA in translation regulation during development. Int. J. Biochem. Cell Biol. 31, 87–106 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Pickering, B. M. & Willis, A. E. The implications of structured 5′ untranslated regions on translation and disease. Semin. Cell Dev. Biol. 16, 39–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Chappell, S. A. et al. A mutation in the c-myc-IRES leads to enhanced internal ribosome entry in multiple myeloma: a novel mechanism of oncogene de-regulation. Oncogene 19, 4437–4440 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Cobbold, L. C. et al. Upregulated c-myc expression in multiple myeloma by internal ribosome entry results from increased interactions with and expression of PTB-1 and YB-1. Oncogene 29, 2884–2891 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Montanaro, L. et al. Novel dyskerin-mediated mechanism of p53 inactivation through defective mRNA translation. Cancer Res. 70, 4767–4777 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Armengol, G. et al. 4E-binding protein 1: a key molecular “funnel factor” in human cancer with clinical implications. Cancer Res. 67, 7551–7555 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Graff, J. R. et al. eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival. Cancer Res. 69, 3866–3873 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Nathan, C. O. et al. Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/mammalian target of rapamycin pathway. Clin. Cancer Res. 10, 5820–5827 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Martín, M. E. et al. 4E binding protein 1 expression is inversely correlated to the progression of gastrointestinal cancers. Int. J. Biochem. Cell Biol. 32, 633–642 (2000).

    Article  PubMed  Google Scholar 

  75. Rousseau, D., Gingras, A. C., Pause, A. & Sonenberg, N. The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth. Oncogene 13, 2415–2420 (1996).

    CAS  PubMed  Google Scholar 

  76. Avdulov, S. 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 5, 553–563 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Jacobson, B. A. 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. 66, 4256–4262 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Wendel, H. G. et al. Dissecting eIF4E action in tumorigenesis. Genes Dev. 21, 3232–3237 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chrestensen, C. A. et al. Loss of MNK function sensitizes fibroblasts to serum-withdrawal induced apoptosis. Genes Cells 12, 1133–1140 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Chrestensen, C. A. et al. MNK1 and MNK2 regulation in HER2-overexpressing breast cancer lines. J. Biol. Chem. 282, 4243–4252 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Culjkovic, B., Topisirovic, I., Skrabanek, L., Ruiz-Gutierrez, M & Borden, K. L. eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3′UTR. J. Cell Biol. 169, 245–256 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Topisirovic, I., Ruiz-Gutierrez, M. & Borden, K. L. Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities. Cancer Res. 64, 8639–8642 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Silva, R. L. & Wendel, H. G. MNK, EIF4E and targeting translation for therapy. Cell Cycle 7, 553–555 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Raught, B. et al. Expression of a translationally regulated, dominant-negative CCAAT/enhancer-binding protein β isoform and up-regulation of the eukaryotic translation initiation factor 2α are correlated with neoplastic transformation of mammary epithelial cells. Cancer Res. 56, 4382–4386 (1996).

    CAS  PubMed  Google Scholar 

  85. Rosenwald, I. B., Hutzler, M. J., Wang, S., Savas, L. & Fraire, A. E. Expression of eukaryotic translation initiation factors 4E and 2α is increased frequently in bronchioloalveolar but not in squamous cell carcinomas of the lung. Cancer 92, 2164–2171 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Wang, S. et al. Expression of eukaryotic translation initiation factors 4E and 2α correlates with the progression of thyroid carcinoma. Thyroid 11, 1101–1107 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Lobo, M. V. et al. Levels, phosphorylation status and cellular localization of translational factor eIF2 in gastrointestinal carcinomas. Histochem. J. 32, 139–150 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Wang, S. et al. Expression of the eukaryotic translation initiation factors 4E and 2α in non-Hodgkin's lymphomas. Am. J. Pathol. 155, 247–255 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Donzé, O., Jagus, R., Koromilas, A. E., Hershey, J. W. & Sonenberg, N. Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. EMBO J. 14, 3828–3834 (1995).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Anderson, P. & Kedersha, N. Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation. Cell Stress Chaperones 7, 213–221 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Fournier, M. J., Gareau, C. & Mazroui, R. The chemotherapeutic agent bortezomib induces the formation of stress granules. Cancer Cell Int. 10, 12 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Arimoto, K., Fukuda, H., Imajoh-Ohmi, S., Saito, H. & Takekawa, M. Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nat. Cell Biol. 10, 1324–1332 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Pataer, A., Swisher, S. G., Roth, J. A., Logothetis, C. J. & Corn, P. G. Inhibition of RNA-dependent protein kinase (PKR) leads to cancer cell death and increases chemosensitivity. Cancer Biol. Ther. 8, 245–252 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Mokas, S. et al. Uncoupling stress granule assembly and translation initiation inhibition. Mol. Biol. Cell 20, 2673–2683 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Johannes, G. & Sarnow, P. Cap-independent polysomal association of natural mRNAs encoding c-myc, BiP, and eIF4G conferred by internal ribosome entry sites. RNA 4, 1500–1513 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Koumenis, C. et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2α. Mol. Cell. Biol. 22, 7405–7416 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhang, K. & Kaufman, R. J. Signaling the unfolded protein response from the endoplasmic reticulum. J. Biol. Chem. 279, 25935–25938 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Kelsen, S. G. et al. Cigarette smoke induces an unfolded protein response in the human lung: a proteomic approach. Am. J. Respir. Cell. Mol. Biol. 38, 541–550 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Jorgensen, E. et al. Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells. BMC Cancer 8, 229 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Scriven, P. et al. Activation and clinical significance of the unfolded protein response in breast cancer. Br. J. Cancer 101, 1692–1698 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang, Q. et al. Overexpression of endoplasmic reticulum molecular chaperone GRP94 and GRP78 in human lung cancer tissues and its significance. Cancer Detect. Prev. 29, 544–551 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Zheng, H. C. et al. Overexpression of GRP78 and GRP94 are markers for aggressive behavior and poor prognosis in gastric carcinomas. Hum.Pathol. 39, 1042–1049 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Su, R. et al. Grp78 promotes the invasion of hepatocellular carcinoma. BMC Cancer 10, 20 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Huang, T. T. et al. Decreased GRP78 protein expression is a potential prognostic marker of oral squamous cell carcinoma in Taiwan. J. Formos. Med. Assoc. 109, 326–337 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Misra, U. K., Deedwania, R. & Pizzo, S. V. Binding of activated α2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J. Biol. Chem. 280, 26278–26286 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Ranganathan, A. C., Zhang, L., Adam, A. P. & Aguirre-Ghiso, J. A. Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res. 66, 1702–1711 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fu, Y., Li, J. & Lee, A. S. GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res. 67, 3734–3740 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Davenport, E. L., Morgan, G. J. & Davies, F. E. Untangling the unfolded protein response. Cell Cycle 7, 865–869 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Porter, J. R., Fritz, C. C. & Depew, K. M. Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy. Curr. Opin. Chem. Biol. 14, 412–420 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Novac, O., Guenier, A. S. & Pelletier, J. Inhibitors of protein synthesis identified by a high throughput multiplexed translation screen. Nucleic Acids Res. 32, 902–915 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Choo, A. Y. & Blenis, J. Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle 8, 567–572 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Kwitkowski, V. E. et al. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 15, 428–435 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Oza, A. M. et al. Phase II study of erlotinib in recurrent or metastatic endometrial cancer: NCIC IND-148. J. Clin. Oncol. 26, 4319–4325 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Hess, G. et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J. Clin. Oncol. 27, 3822–3829 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Smith, S. M. et al. Activity of single agent temsirolimus (CCI-779) in non-mantle cell non-Hodgkin lymphoma subtypes [abstract]. J. Clin. Oncol. 26, a8514 (2008).

    Article  Google Scholar 

  116. Pandya, K. J. et al. Eastern Cooperative Oncology Group (E1500). A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500). J. Thorac. Oncol. 2, 1036–1041 (2007).

    Article  PubMed  Google Scholar 

  117. Chan, S. et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J. Clin. Oncol. 23, 5314–5322 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Guertin, D. A. & Sabatini, D. M. The pharmacology of mTOR inhibition. Sci. Signal. 2, pe24 (2009).

    Article  PubMed  Google Scholar 

  119. Feldman, M. E. et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7, e38 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Hsieh, A. C. et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 17, 249–261 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wan, X., Harkavy, B., Shen, N., Grohar, P. & Helman, L. J. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26, 1932–1940 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Park, S. et al. RIP1 activates PI3K-Akt via a dual mechanism involving NF-kappaB-mediated inhibition of the mTOR-S6K-IRS1 negative feedback loop and down-regulation of PTEN. Cancer Res. 6 9, 4107–4111 (2009).

    Article  CAS  Google Scholar 

  123. Tschopp, C. et al. Phosphorylation of eIF-4E on ser 209 in response to mitogenic and inflammatory stimuli is faithfully detected by specific antibodies. Mol. Cell. Biol. Res. Commun. 3, 205–211 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Zhang, M. et al. Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia and overcomes imatinib resistance. Mol. Cell. Biol. 28, 6496–6509 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Wang, X. et al. Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation. Mol. Cell. Biol. 27, 7405–7413 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Juliano, R., Bauman, J., Kang, H. & Ming, X. Biological barriers to therapy with antisense and siRNA oligonucleotides. Mol. Pharm. 6, 686–695 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Agrawal, S. & Kandimalla, E. R. Antisense and/or immunostimulatory oligonucleotide therapeutics. Curr. Cancer Drug Targets 1, 197–209 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Graff, J. R. et al. Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. J. Clin. Invest. 117, 2638–2648 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Moerke, N. J. et al. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 128, 257–267 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Fan, S., Li, Y., Yue, P., Khuri, F. R. & Sun, S. Y. 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 12, 346–356 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Kentsis, A., Topisirovic, I., Culjkovic, B., Shao, L. & Borden, K. L. Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc. Natl Acad. Sci. USA 101, 18105–18110 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kentsis, A. et al. Further evidence that ribavirin interacts with eIF4E. RNA 11, 1762–1766 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Westman, B. et al. The antiviral drug ribavirin does not mimic the 7-methylguanosine moiety of the mRNA cap structure in vitro. RNA 11, 1505–1513 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Yan, Y., Svitkin, Y., Lee, J. M., Bisaillon, M. & Pelletier, J. Ribavirin is not a functional mimic of the 7-methyl guanosine mRNA cap. RNA 11, 1238–1244 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Assouline, S. et al. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood 114, 257–260 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Borden, K. L. & Culjkovic-Kraljacic, B. Ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond? Leuk. Lymphoma 51, 1805–1815 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Northcote, P. T., Blunt, J. W. & Munro, M. H. G. Pateamine: a potent cytotoxin from the New Zealand marine sponge, mycale sp. Tetrahedron Lett. 32, 6411–6414 (1991).

    Article  CAS  Google Scholar 

  138. Bordeleau, M. E. et al. RNA-mediated sequestration of the RNA helicase eIF4A by Pateamine A inhibits translation initiation. Chem. Biol. 13, 1287–95 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Low, W. K. et al. Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. Mol. Cell. 20, 709–722 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Dang, Y. et al. Eukaryotic initiation factor 2α-independent pathway of stress granule induction by the natural product pateamine A. J. Biol. Chem. 281, 32870–32878 (2006).

    Article  CAS  PubMed  Google Scholar 

  141. Kuznetsov, G. et al. Potent in vitro and in vivo anticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A. Mol. Cancer Ther. 8, 1250–1260 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Lindqvist, L. et al. Selective pharmacological targeting of a DEAD box RNA helicase. PLoS ONE 3, e1583 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Bordeleau, M. E. et al. Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A. Nat. Chem. Biol. 2, 213–220 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. González, N., Barral, M. A., Rodríguez, J & Jiménez, C. New cytotoxic steroids from the gorgonian Isis hippuris. Structure–activity studies. Tetrahedron 57, 3487–3497 (2001).

    Article  Google Scholar 

  145. Ravindar, K. et al. Efficient synthetic approach to potent antiproliferative agent hippuristanol via Hg(II)-catalyzed spiroketalization. Org. Lett. 12, 4420–4423 (2010).

    Article  CAS  PubMed  Google Scholar 

  146. Li, W., Dang, Y., Liu, J. O. & Yu, B. Expeditious synthesis of hippuristanol and congeners with potent antiproliferative activities. Chemistry 15, 10356–10359 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Hwang, B. Y. et al. Silvestrol and episilvestrol, potential anticancer rocaglate derivatives from Aglaia silvestris. J. Org. Chem. 69, 3350–3358 (2004).

    Article  CAS  PubMed  Google Scholar 

  148. Cencic, R. et al. Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol. PLoS ONE 4, e5223 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Cencic, R. et al. Synergistic effect of inhibiting translation initiation in combination with cytotoxic agents in acute myelogenous leukemia cells. Leuk. Res. 34, 535–541 (2010).

    Article  CAS  PubMed  Google Scholar 

  150. Lucas, D. M. et al. The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. Blood 113, 4656–4666 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Chen, R. & Plunkett, W. Strategy to induce apoptosis and circumvent resistance in chronic lymphocytic leukaemia. Best Pract. Res. Clin. Haematol. 23, 155–166 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Lucas, D. M. et al. Potential of plant-derived natural products in the treatment of leukemia and lymphoma. Curr. Drug Targets 11, 812–822 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Matsuo, J. et al. Preventing the unfolded protein response via aberrant activation of 4E-binding protein 1 by versipelostatin. Cancer Sci. 100, 327–333 (2008).

    Article  CAS  Google Scholar 

  154. Kim, J. Y. et al. Arctigenin blocks the unfolded protein response and shows therapeutic antitumor activity. J. Cell. Physiol. 224, 33–40 (2010).

    CAS  PubMed  Google Scholar 

  155. Misra, U. K. & Pizzo, S. V. Modulation of the unfolded protein response in prostate cancer cells by antibody-directed against the carboxyl-terminal domain of GRP78. Apoptosis 15, 173–182 (2010).

    Article  CAS  PubMed  Google Scholar 

  156. Yoneda, Y. et al. A cell-penetrating peptidic GRP78 ligand for tumor cell-specific prodrug therapy. Bioorg. Med. Chem. Lett. 18, 1632–1636 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    Article  CAS  PubMed  Google Scholar 

  158. Cannell, I. G., Kong, Y. W. & Bushell, M. How do microRNAs regulate gene expression? Biochem. Soc. Trans. 36, 1224–1231 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Zhang, W., Dahlberg, J. E. & Tam, W. MicroRNAs in tumorigenesis: a primer. Am. J. Pathol. 171, 728–738 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Garzon, R., Marcucci, G. & Croce, C. M. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat. Rev. Drug Discov. 9, 775–789 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Drygin, D., Rice, W. G. & Grummt, I. The RNA polymerase I transcription machinery: an emerging target for the treatment of cancer. Annu. Rev. Pharmacol. Toxicol. 50, 131–156 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Drygin, D. et al. Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. Cancer Res. 69, 7653–7661 (2009).

    Article  CAS  PubMed  Google Scholar 

  163. Robert, F. et al. Altering chemosensitivity by modulating translation elongation. PLoS ONE 4, e5428 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Wang, Y. et al. DCB-3503, a tylophorine analog, inhibits protein synthesis through a novel mechanism. PLoS ONE 5, e11607 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Mitkevich, V. A. et al. Termination of translation in eukaryotes is mediated by the quaternary eRF1*eRF3*GTP*Mg2+ complex. The biological roles of eRF3 and prokaryotic RF3 are profoundly distinct. Nucleic Acids Res. 34, 3947–3954 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Malta-Vacas, J. et al. Differential expression of the eukaryotic release factor 3 (eRF3/GSPT1) according to gastric cancer histological types. J. Clin. Pathol. 58, 621–625 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Chu, R. et al. Selective concomitant inhibition of mTORC1 and mTORC2 activity in estrogen receptor negative breast cancer cells by BN107 and oleanolic acid. Int. J. Cancer 127, 1209–1219 (2010).

    Article  CAS  PubMed  Google Scholar 

  168. Park, H. R. et al. Effect on tumor cells of blocking survival response to glucose deprivation. J. Natl Cancer Inst. 96, 1300–1310 (2004).

    Article  CAS  PubMed  Google Scholar 

  169. Raught, B. et al. Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI. EMBO J. 19, 434–444 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Jennings, M. D. & Pavitt, G. D. eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation. Nature 465, 378–381 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Figure 1 was provided by Laura Cobbold (MRC Toxicology Unit, University of Leicester, UK).

Author information

Authors and Affiliations

  1. Department of Oncology, Imperial College Hammersmith Campus, Du Cane Road, London, W12 0HS, UK

    Sarah P. Blagden

  2. Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester, LE1 7RH, UK

    Anne E. Willis

Authors
  1. Sarah P. Blagden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne E. Willis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S. P. Blagden researched the data for the article, writing the article and reviewed and/or edited the manuscript before submission. A. E. Willis made a substantial contribution to the discussion of the content and the review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Sarah P. Blagden.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blagden, S., Willis, A. The biological and therapeutic relevance of mRNA translation in cancer. Nat Rev Clin Oncol 8, 280–291 (2011). https://doi.org/10.1038/nrclinonc.2011.16

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2011.16

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer