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The interplay between cell signalling and the mevalonate pathway in cancer

Nature Reviews Cancer volume 16, pages 718–731 (2016)Cite this article

Subjects

Key Points

  • Mevalonate (MVA) pathway metabolites are essential for cancer cell survival and growth.

  • Expression of the genes encoding MVA pathway enzymes is controlled by the sterol regulatory element-binding protein (SREBP) family of transcription factors.

  • In cancer cells, oncogenic signalling pathways deregulate the activity of the SREBP transcription factors and MVA pathway enzymes.

  • Deregulated production of MVA pathway metabolites modulates multiple signalling pathways in cancer cells and contributes to transformation.

  • Clinical trials to evaluate the utility of MVA pathway inhibitors as anticancer agents have shown responses in some, but not all, patients; discovering biomarkers to identify responders and developing combination therapies will further enhance the utility of these inhibitors.

  • Inhibiting the SREBP transcription factors is a promising strategy to increase the efficacy of MVA pathway inhibitors as anticancer therapeutics, and also potentially to combat resistance to MVA pathway therapies.

Abstract

The mevalonate (MVA) pathway is an essential metabolic pathway that uses acetyl-CoA to produce sterols and isoprenoids that are integral to tumour growth and progression. In recent years, many oncogenic signalling pathways have been shown to increase the activity and/or the expression of MVA pathway enzymes. This Review summarizes recent advances and discusses unique opportunities for immediately targeting this metabolic vulnerability in cancer with agents that have been approved for other therapeutic uses, such as the statin family of drugs, to improve outcomes for cancer patients.

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Figure 1: Overview of the MVA pathway.
Figure 2: The chemical reactions of the MVA pathway.
Figure 3: The SREBP-regulated sterol feedback response controls the transcription of MVA pathway (and other) genes.
Figure 4: SREBP processing and activity are regulated by PI3K signalling at multiple levels.
Figure 5: Transcriptional control of MVA pathway gene transcription by oncogenes and tumour suppressors.
Figure 6: Activation of the MVA pathway drives oncogenic signalling pathways.
Figure 7: Inhibition of both the MVA pathway and the SREBP transcription factors is a viable cancer therapeutic strategy.

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Acknowledgements

The authors thank J. van Leeuwen and W. B. Tu for helping to prepare this Review. The authors also thank other current and former members of the Penn laboratory for their helpful comments, including A. Pandyra, E. Chamberlain, J. De Melo, D. Dingar, A. Hickman, M. Kalkat, C. Lourenco, D. Resetca and A. Tamachi. The authors also acknowledge the many important contributions by their colleagues that could not be cited here owing to space and reference constraints. The funding agencies that enable the authors' research include the Ontario Institute for Cancer Research through funding provided by the Province of Ontario, the Canadian Institute for Health Research, Prostate Cancer Canada, the Department of Defense Breast Cancer Research Program, the Princess Margaret Cancer Foundation Hold'em for Life Prostate Cancer Research Fund, and the Terry Fox Foundation Canada. L.Z.P. holds the Canada Research Chair in Molecular Oncology.

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  1. Peter J. Mullen, Rosemary Yu and Joseph Longo: These authors contributed equally to this work.

Authors and Affiliations

  1. Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, Ontario, Canada

    Peter J. Mullen, Rosemary Yu, Joseph Longo & Linda Z. Penn

  2. Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, M5G 1L7, Ontario, Canada

    Rosemary Yu, Joseph Longo, Michael C. Archer & Linda Z. Penn

  3. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, M5S 3E2, Ontario, Canada

    Michael C. Archer

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PowerPoint slides

Glossary

Acetyl-CoA

An essential metabolite that is used to drive many cellular processes, including the tricarboxylic acid (TCA) cycle, fatty acid and sterol biosynthesis, and acetylation of histones.

SREBP cleavage-activating protein

(SCAP). Essential for sterol regulatory element-binding protein (SREBP) endoplasmic reticulum (ER)-to-Golgi translocation. SCAP contains a sterol-sensing domain and undergoes a conformational change when levels of ER membrane sterols are low. This change causes a dissociation of the SCAP–SREBP complex from insulin-induced genes (INSIGs).

Insulin-induced genes

(INSIGs). INSIG1 and INSIG2 interact with SREBP cleavage-activating protein (SCAP) under sterol-rich conditions. They prevent sterol regulatory element-binding protein (SREBP) activation by retaining the SCAP–SREBP complex in the endoplasmic reticulum (ER). They also promote the sterol-regulated degradation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR).

Site-1 protease and site-2 protease

(S1P and S2P). Two proteases that cleave the sterol regulatory element-binding proteins (SREBPs), in the Golgi. S1P cleaves at the luminal loop of the SREBPs, whereas S2P is a hydrophobic protein that cleaves the SREBPs at a transmembrane residue.

Sterol regulatory elements

(SREs). Motifs found in the promoters of genes that are transcribed in response to sterol deprivation. SREs are necessary for the transcription of mevalonate (MVA) pathway genes by the sterol regulatory element-binding proteins (SREBPs).

Lipid rafts

Membrane domains that contain high concentrations of cholesterol, saturated fatty acids and sphingolipids. They are tightly packed and form the liquid ordered phase of membranes. One key role is to enable protein complexes to be pre-organized for efficient signal transduction.

γδ T cells

T cells with a T cell receptor that contains a γ- and a δ-chain instead of the more common α- and β-chains. They are known to recognize lipid antigens, are independent of major histocompatibility complex (MHC) class I presentation and are currently being investigated for their anticancer potential.

Isoprenylation

The attachment of a hydrophobic farnesol or geranygeraniol to the carboxyl terminus of proteins that contain a CAAX motif, which anchors the proteins to lipid membranes. Geranylgeraniol can also be attached to non-CAAX motif-containing proteins.

Quinone

A cyclic organic compound that contains two C=O groups. The quinone coenzyme Q is derived from the essential amino acid tyrosine.

C-Cell adenoma

C-Cells (also known as parafollicular cells) are found in the thyroid and produce the hormone calcitonin. Tumours originating from the C-cells include medullary thyroid cancer, and mutations in the RET proto-oncogene are often found in patients.

Aromatase inhibitors

Inhibitors of oestrogen production and a common treatment option for patients with oestrogen receptor-positive breast cancer.

Ki67 index

The fraction of Ki67-positive tumour cells as determined using immunohistochemistry. The expression of Ki67 is associated with cell proliferation.

Dipyridamole

A clinically approved drug used to prevent platelet aggregation.

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Mullen, P., Yu, R., Longo, J. et al. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer 16, 718–731 (2016). https://doi.org/10.1038/nrc.2016.76

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