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Open Access Research

Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells

Liang Zheng1, Elaine D MacKenzie1, Saadia A Karim1, Ann Hedley1, Karen Blyth1, Gabriela Kalna1, David G Watson2, Peter Szlosarek34, Christian Frezza15* and Eyal Gottlieb1

Author Affiliations

1 Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow, G61 1BD, UK

2 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, G4 0NR, Glasgow, UK

3 Queen Mary, University of London, Barts and The London School of Medicine, Charterhouse Square, London, EC1M 6BQ, UK

4 Department of Medical Oncology, St Bartholomew’s Hospital, West Smithfield, London, EC1A 7BE, UK

5 Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge, CB2 OXZ, UK

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Cancer & Metabolism 2013, 1:12  doi:10.1186/2049-3002-1-12

Published: 21 March 2013

Abstract

Background

Loss of function of fumarate hydratase (FH), the mitochondrial tumor suppressor and tricarboxylic acid (TCA) cycle enzyme, is associated with a highly malignant form of papillary and collecting duct renal cell cancer. The accumulation of fumarate in these cells has been linked to the tumorigenic process. However, little is known about the overall effects of the loss of FH on cellular metabolism.

Methods

We performed comprehensive metabolomic analyses of urine from Fh1-deficient mice and stable isotopologue tracing from human and mouse FH-deficient cell lines to investigate the biochemical signature of the loss of FH.

Results

The metabolomics analysis revealed that the urea cycle metabolite argininosuccinate is a common metabolic biomarker of FH deficiency. Argininosuccinate was found to be produced from arginine and fumarate by the reverse activity of the urea cycle enzyme argininosuccinate lyase (ASL), making these cells auxotrophic for arginine. Depleting arginine from the growth media by the addition of pegylated arginine deiminase (ADI-PEG 20) decreased the production of argininosuccinate in FH-deficient cells and reduced cell survival and proliferation.

Conclusions

These results unravel a previously unidentified correlation between fumarate accumulation and the urea cycle enzyme ASL in FH-deficient cells. The finding that FH-deficient cells become auxotrophic for arginine opens a new therapeutic perspective for the cure of hereditary leiomyomatosis and renal cell cancer (HLRCC).

Keywords:
HLRCC; Renal cancer; Fumarate hydratase; Argininosuccinate; Metabolomics