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Translational control in cancer

Nature Reviews Cancer volume 10, pages 254–266 (2010)Cite this article

Subjects

Key Points

  • Alterations in the expression and activity of specific translation factors, and the uncoupling of translational regulation from inhibition by tumour cell stresses, such as hypoxia and nutrient deprivation, are a common feature of human cancers. These alterations are associated with specific types of human cancers and different stages of disease and cellular transformation.

  • Most, if not all, of the pathways that are crucial for cancer development and progression affect translational control. These include the selective translation of mRNAs encoding proteins that are engaged in tumour cell proliferation, growth, angiogenesis, response to mitogenic stimuli and the tumour microenvironment, and tumour stress responses such as hypoxia and nutrient deprivation.

  • Targeting specific translation factors that are altered in expression or activity in human cancers, and the specialized mRNA translation elements used preferentially in tumours, offers great promise for the development of a new generation of cancer therapeutics.

Abstract

Remarkable progress has been made in defining a new understanding of the role of mRNA translation and protein synthesis in human cancer. Translational control is a crucial component of cancer development and progression, directing both global control of protein synthesis and selective translation of specific mRNAs that promote tumour cell survival, angiogenesis, transformation, invasion and metastasis. Translational control of cancer is multifaceted, involving alterations in translation factor levels and activities unique to different types of cancers, disease stages and the tumour microenvironment. Several clinical efforts are underway to target specific components of the translation apparatus or unique mRNA translation elements for cancer therapeutics.

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Figure 1: Eukaryotic cap-dependent mRNA translation.
Figure 2: A cap-dependent to cap-independent translation switch mediated by the Akt–mTOR–4E-BP pathway.
Figure 3: Key signal transduction pathways that regulate protein synthesis.

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Acknowledgements

Department of Defense Breast Cancer Research grant W81XWH-04-1 (R.J.S. and S.C.F.), Breast Cancer Research Foundation grant (R.J.S. and S.C.F.) and New York State Health grant (D.S.).

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Authors and Affiliations

  1. Department of Microbiology, New York, 10016, New York, USA

    Deborah Silvera, Silvia C. Formenti & Robert J. Schneider

  2. Radiation Oncology, New York, 10016, New York, USA

    Silvia C. Formenti & Robert J. Schneider

  3. NYU Cancer Institute, New York University School of Medicine, New York, 10016, New York, USA

    Silvia C. Formenti & Robert J. Schneider

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Glossary

Eμ-Myc lymphomagenesis mouse model

One of the first mouse cancer models, it uses overexpression of Myc in B cells of these mice driven by the immunoglobulin heavy chain enhancer (Eμ).

Polyribosome

An mRNA–ribosome complex that generally contains actively translating mRNAs bound to multiple 80S ribosomes. The greater the number of ribosomes associated with an mRNA the greater the translation activity of the mRNA.

m7GpppN cap

A post-transcriptional, covalently linked inverted m7GTP (m7G) attached to the first 5′ nucleotide (N) of the mRNA. It protects the mRNA from degradation and binds eIF4E, recruiting eIF4F and 40S ribosome subunits.

Unfolded protein response

A cellular response to stress that is unique to the endoplasmic reticulum (ER), and which senses the misfolding of proteins in the ER. It activates pathways that help cells survive proteotoxicity caused by unfolded proteins or activate mechanisms of cell death.

Tumour quiescence

A mechanism whereby tumour cells can adapt by genetic and epigenetic alterations to unfavourable conditions in the microenvironment before proliferating again.

Gleason score

Pathological classification of the grade of prostate cancer. A lower score indicates a well-differentiated tumour with slower growth. A higher score indicates a poorly differentiated tumour with aggressive growth.

Mouse mammary tumour virus (MMTV)

MMTV causes mammary adenocarcinoma in infected mice and selectively replicates in the alveolar epithelial cells of the mammary gland. The MMTV promoter and enhancer are often used to direct the expression of transgenes specifically in the mammary gland.

Mouse tumour xenograft models

Hetero-transplantation of human tumour cells into immunodeficient mice, in either the orthotopic (same organ) site or ectopic (foreign) site. Mice are typically athymic nu/nu T cell deficient or severe combined immunodeficient (SCID), lacking B cell and T cell functions.

BCR–ABL

A leukaemogenic fusion protein that is a result of reciprocal translocation between chromosome 9 and chromosome 22. The 5′ section of BCR from chromosome 9 is fused to most of the proto-oncogene ABL from chromosome 22.

5′ untranslated region (5′UTR)

Also known as the 5′ noncoding region in eukaryotes, this includes the region of the mRNA from the transcription start site (m7GpppN cap) to the start of translation initiation, typically an AUG codon.

Internal ribosome entry site (IRES)

A nucleotide sequence in the mRNA 5′ noncoding region that confers internal ribosome initiation of translation without eIF4E but typically with other initiation factors, bypassing the m7GpppN cap and cap-dependent regulation.

Flavagline drug

A strong cell cycle inhibiting chemotherapeutic flavonol-cinnamate drug, a natural product of the plant genus Aglaia. It impairs ribosome recruitment by acting on eIF4A.

Rapamycin

An immunosuppressive drug that inhibits mTOR. Rapamycin and other mTOR inhibitors are being assessed as potential therapeutics in several cancers.

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Silvera, D., Formenti, S. & Schneider, R. Translational control in cancer. Nat Rev Cancer 10, 254–266 (2010). https://doi.org/10.1038/nrc2824

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