Review Article | Published:

Rewiring urea cycle metabolism in cancer to support anabolism

Nature Reviews Cancervolume 18pages634645 (2018) | Download Citation


Cancer cells reprogramme metabolism to maximize the use of nitrogen and carbon for the anabolic synthesis of macromolecules that are required during tumour proliferation and growth. To achieve this aim, one strategy is to reduce catabolism and nitrogen disposal. The urea cycle (UC) in the liver is the main metabolic pathway to convert excess nitrogen into disposable urea. Outside the liver, UC enzymes are differentially expressed, enabling the use of nitrogen for the synthesis of UC intermediates that are required to accommodate cellular needs. Interestingly, the expression of UC enzymes is altered in cancer, revealing a revolutionary mechanism to maximize nitrogen incorporation into biomass. In this Review, we discuss the metabolic benefits underlying UC deregulation in cancer and the relevance of these alterations for cancer diagnosis and therapy.

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A.E. is the incumbent of the Leah Omenn Career Development Chair and is supported by research grants from the European Research Program (CIG618113 and ERC614204), the Israel Science Foundation (1343/13 and 1952/13) and a Minerva grant award (711730). A.E. received additional support from the Adelis Foundation, the Henry S. and Anne S. Reich Research Fund, the Dukler Fund for Cancer Research, the Paul Sparr Foundation, the Saul and Theresa Esman Foundation, Joseph Piko Baruch and the estate of Fannie Sherr. R.K. is supported by the Rising Tide Foundation (721543). P.S. is supported by the Higher Education Funding Council for England and research grants from Cancer Research UK, British Lung Foundation, Barts Charity and Polaris Pharma. The work of A.C. is supported by the Basque Department of Industry, Tourism and Trade (Etortek) and the Department of Education (IKERTALDE IT1106-16), the Spanish Association Against Cancer (AECC, IDEAS175CARR), the Banco Bilbao Vizcaya Argentaria (BBVA) foundation, the Ministerio de Economía y Competitividad (MINECO) (SAF2016-79381-R (Fondo Europeo de Desarrollo Regional (FEDER)/European Union (EU)); Severo Ochoa Excellence Accreditation SEV-2016-0644) and the European Commission (European Research Council (ERC) Starting Grant 336343, ERC Proof of Concept 754627, H2020-MSCA-ITN 721532). CIBERONC was co-funded with FEDER funds.

Reviewer information

Nature Reviews Cancer thanks C. Frezza and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    • Rom Keshet
    •  & Ayelet Erez
  2. Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK

    • Peter Szlosarek
  3. Barts Health NHS Trust, St Bartholomew’s Hospital, London, UK

    • Peter Szlosarek
  4. CIC bioGUNE, Bizkaia, Spain

    • Arkaitz Carracedo
  5. CIBERONC, Instituto de Salud Carlos III, Madrid, Spain

    • Arkaitz Carracedo
  6. Ikerbasque, Basque Foundation for Science, Bilbao, Spain

    • Arkaitz Carracedo
  7. Biochemistry and Molecular Biology Department, University of the Basque Country, Bilbao, Spain

    • Arkaitz Carracedo


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A.E., P.S. and A.C. researched data for the article, substantially contributed to the discussion of content, contributed to writing the article and generating the figures and reviewed and edited the manuscript before submission. R.K. researched data for the article and contributed to writing the article and generating the figures.

Competing interests

P.S. receives research funding support and is an investigator on clinical trials of PEGylated arginine deaminase (ADI-PEG20) from Polaris Pharma.

Corresponding author

Correspondence to Ayelet Erez.

Supplementary information



The process of replenishing depleted metabolic cycle or pathway intermediates.

Aspartate transcarbamylase

An enzyme that catalyses the formation of carbamoyl aspartic acid and inorganic phosphate from aspartate and carbamoyl phosphate (CP), which is the first step in pyrimidine synthesis.


An enzyme that catalyses the formation of 4,5-dihydroorotic acid from carbamoyl aspartic acid during pyrimidine synthesis.


An aromatic ring composed of two nitrogen atoms and four carbon atoms, from which derive the three nitrogenous bases thymine, uracil and cytosine.


The restriction of a cellular component or process within a defined cellular compartment, such as the cytosol or a specific organelle.

Pyruvate carboxylase

A mitochondrial enzyme that catalyses the formation of oxaloacetate from pyruvate. The reaction is irreversible. Oxaloacetate can replenish the tricarboxylic acid cycle or be used for gluconeogenesis.

Fumarate hydratase

(FH). An enzyme that catalyses the hydration of fumarate to malate in the tricarboxylic acid cycle (mitochondrial isoform) or as a reaction contributing to fumarate and amino acid metabolism in the cytosol (cytosolic isoform). The reaction is reversible.

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