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  • Review Article
  • Published:

Targeting the translation machinery in cancer

Nature Reviews Drug Discovery volume 14, pages 261–278 (2015)Cite this article

Subjects

Key Points

  • Dysregulation of mRNA translation is a frequent feature of neoplasia. As the components of the translation machinery integrate almost all oncogenic signals, targeting the protein synthesis machinery holds promise for overcoming therapeutic issues associated with intra-tumour heterogeneity.

  • Many translation initiation factors, including the subunits of the eukaryotic translation initiation factor 4F (eIF4F) complex, were found to be dysregulated in various cancers. Increased eIF4E levels and/or availability for eIF4F assembly, as well as increased eIF4E phosphorylation, are observed in various malignancies and are associated with poor prognosis.

  • Increased levels of the eIF4F complex render cancer cells resistant to chemotherapeutics (for example, doxorubicin) and targeted therapies (for example, mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase–mammalian target of rapamycin (PI3K–mTOR) inhibitors), suggesting that the 'addiction' of drug-resistant cancer cells to eIF4F represents a vulnerability that could be clinically exploited.

  • Allosteric inhibitors of mTOR complex 1 (mTORC1), such as rapamycin and rapamycin analogues, or rapalogues, are approved for treatment of various human cancers; however, their efficacy has been lower than expected. Active-site mTOR inhibitors (asTORi) are more potent inhibitors of mTOR, show superior anti-neoplastic effects in preclinical models, and are under investigation in clinical trials.

  • Direct inhibition of eIF4F is being investigated in preclinical and clinical settings (for example, eIF4E antisense oligonucleotides, inhibitors of eIF4E–5′-mRNA-cap and eIF4E–eIF4G interaction, and inhibitors of eIF4A). In particular, eIF4A inhibitors display impressive anti-neoplastic effects, with efforts underway to improve their pharmacodynamics for use in the clinic.

Abstract

Dysregulation of mRNA translation is a frequent feature of neoplasia. Many oncogenes and tumour suppressors affect the translation machinery, making aberrant translation a widespread characteristic of tumour cells, independent of the genetic make-up of the cancer. Therefore, therapeutic agents that target components of the protein synthesis apparatus hold promise as novel anticancer drugs that can overcome intra-tumour heterogeneity. In this Review, we discuss the role of translation in cancer, with a particular focus on the eIF4F (eukaryotic translation initiation factor 4F) complex, and provide an overview of recent efforts aiming to 'translate' these results to the clinic.

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Figure 1: Overview of translation initiation.
Figure 2: The translation apparatus has a pivotal role in mediating the effects of commonly dysregulated oncogenic signalling pathways in cancer.
Figure 3: Therapeutic agents being investigated to target the translation machinery in cancer.
Figure 4: Upstream signalling inhibitors.
Figure 5: Direct inhibitors of the translation machinery.
Figure 6: Other inhibitors.

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Acknowledgements

The authors thank P. Roux, V. Gandin and N. Siddiqui for their critical review of this manuscript. M.B. is a recipient of the Canadian Institutes for Health Research (CIHR) Fellowship for Health Professionals. N.R. is a recipient of the Vanier Canada Graduate Scholarship. J.P. is supported by CIHR grants (MOP-106530 and MOP-115126). N.S. is supported by the Susan G. Komen Breast Cancer Foundation (IIR12224057), CIHR MOP-7214, the Canadian Cancer Society Research Institute (#702317) and the Howard Hughes Medical Institute (#55007654). I.T. is supported by CIHR MOP-115195, a Cancer Research Society operating grant, the Swedish Foundation for International Cooperation in Research and Higher Education, a CIHR Young Investigator Award, and the Fonds de Recherche du Québec-Santé.

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Author notes

  1. Mamatha Bhat, Nathaniel Robichaud and Laura Hulea: These authors contributed equally to this work.

Authors and Affiliations

  1. Goodman Cancer Research Centre, 1160 Pine Avenue West, Montreal, H3A 1A3, Quebec, Canada

    Mamatha Bhat, Nathaniel Robichaud, Nahum Sonenberg & Jerry Pelletier

  2. Division of Gastroenterology, McGill University Health Centre, 687 Pine Avenue West, Montreal, H3A1A1, Quebec, Canada

    Mamatha Bhat

  3. Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, H3G 1Y6, Quebec, Canada

    Nathaniel Robichaud, Nahum Sonenberg & Jerry Pelletier

  4. Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte-Ste-Catherine Road, Montreal, H3T 1E2, Quebec, Canada

    Laura Hulea & Ivan Topisirovic

  5. Department of Oncology, McGill University, 546 Pine Avenue West, Montreal, H2W 1S6, Quebec, Canada

    Laura Hulea & Ivan Topisirovic

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  1. Mamatha Bhat
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Dysregulation of Translation Initiation Factors and Regulators in Human Cancers. (PDF 296 kb)

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Glossary

mRNA translation

A process whereby proteins are synthesized from mRNAs by the orchestrated action of ribosomes, tRNAs and auxiliary proteins. Translation occurs in four distinct phases: initiation (positioning of the translation-competent ribosome on the initiator codon of mRNA), elongation (incorporation of amino acids into a growing polypeptide chain), termination (release of synthesized polypeptides from the ribosome) and ribosome recycling (dissociation of ribosomes and auxiliary factors to release free ribosomal subunits).

Translation initiation

The first and generally rate-limiting step of translation, during which initiation factors facilitate positioning of the translation-competent ribosome at the initiation codon of the mRNA. Most translational control occurs at this step.

Intra-tumour heterogeneity

The existence of multiple genetically heterogeneous clones of cancer cells in the same tumour bed that probably evolved through branched evolution. Intra-tumour heterogeneity hampers therapies that are tailored to target specific 'driver mutations' as cancer cells in the same tumour can be driven by several different oncogenic pathways.

Eukaryotic translation initiation factor 4F complex

(eIF4F complex). A heterotrimeric complex composed of a 5′ mRNA cap-binding subunit eIF4E, the large scaffolding protein eIF4G, and the ATP-dependent RNA helicase eIF4A. The eIF4F complex recruits the mRNA to the ribosome and facilitates its scanning of the 5′ untranslated region (5′UTR) in search of an initiation codon.

43S pre-initiation complex

(43S PIC). A large multifactorial complex formed by association of the 40S ribosomal subunit with eukaryotic translation initiation factors (eIFs) eIF1, eIF1A, eIF3, eIF5 and the ternary complex. The 43S PIC is recruited to the mRNA by the eIF4F complex, which leads to formation of the 48S initiation complex.

eIF4E-sensitive mRNAs

The subset of mRNAs for which translation is disproportionately affected by changes in eIF4E levels. Most of these mRNAs encode proteins that promote proliferation, survival, invasion and metastasis. A selective increase in the expression of tumorigenic factors encoded by eIF4E-sensitive mRNAs underpins the oncogenic activity of eIF4E.

Mammalian target of rapamycin

(mTOR). A serine/threonine kinase that integrates extracellular signals and intracellular cues to regulate proliferation, growth, protein synthesis, metabolic programmes and autophagy via a multitude of substrates. mTOR exists as two functionally and structurally divergent complexes, mTOR complex 1 (mTORC1) and mTORC2. mTORC1 stimulates translation by phosphorylating 4E-binding proteins and S6 kinases.

4E-binding proteins

(4E-BPs). Small translational suppressors that impede eukaryotic translation initiation factor 4F (eIF4F) assembly by competing with eIF4G for binding to eIF4E. Mammalian target of rapamycin complex 1 (mTORC1) phosphorylates 4E-BPs at multiple sites, which leads to their dissociation from eIF4E, facilitating assembly of the eIF4F complex. 4E-BP1, 4E-BP2 and 4E-BP3 are present in mammals.

MAPK-interacting kinases

(MNKs). Kinases that regulate eukaryotic translation initiation factor 4E (eIF4E) by phosphorylating it at a single site (Ser209 in mammals). MNKs are activated downstream of the MEK–ERK (MAPK/ERK kinase–extracellular signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) pathways in response to mitogenic signals or stress. Phosphorylation of eIF4E stimulates translation of a subset of mRNAs encoding invasion-promoting and metastasis-promoting proteins and cytokines.

Rapamycin

A macrolide that associates with mammalian target of rapamycin (mTOR) in a complex with the immunophilin FKBP12, resulting in allosteric modifications in mTOR that lead to its dissociation from the mTOR complex 1 (mTORC1)-specific component RAPTOR (regulatory associated protein of mTOR). This is thought to be the mechanism of selective inhibition of mTORC1, but not mTORC2, by acute rapamycin treatment. In several cell lines and hepatocytes in vivo, prolonged rapamycin treatment also inhibits mTORC2. Rapamycin analogues (rapalogues) work in a similar way.

Active-site mTOR inhibitors

(asTORi). ATP-competitive inhibitors that suppress both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 signalling by blocking the active site of mTOR.

Ternary complex

(TC). A complex of eIF2 (containing α, β and γ subunits), initiator tRNAMet and GTP.

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Bhat, M., Robichaud, N., Hulea, L. et al. Targeting the translation machinery in cancer. Nat Rev Drug Discov 14, 261–278 (2015). https://doi.org/10.1038/nrd4505

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