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Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells.


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Authors

Zheng, Liang 
MacKenzie, Elaine D 
Karim, Saadia A 
Hedley, Ann 
Blyth, Karen 

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).

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Keywords

1112 Oncology and Carcinogenesis, 0601 Biochemistry and Cell Biology, Biomedical, Basic Science, Cancer, Kidney Disease, Rare Diseases, Cancer, 2.1 Biological and endogenous factors

Journal Title

Cancer Metab

Conference Name

Journal ISSN

2049-3002
2049-3002

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_UU_12022/6)