Loss of function of the mitochondrial tumor suppressor fumarate hydratase (FH) is associated with renal cell cancer, and a build-up of fumarate in these cells has been linked to tumorigenesis. In a recent study published in Cancer & Metabolism, Eyal Gottlieb’s team at the Beatson Institute for Cancer Research in Glasgow, UK, have used metabolomic techniques to investigate the cellular metabolic changes caused by loss of FH activity. They first confirmed that deletion of the FH gene causes kidney cancer in a mouse model and then analyzed the urine of mice lacking FH; they identified fumarate and, unexpectedly, the metabolite argininosuccinate as major secretion products in these mice. In order to understand how argininosuccinate was generated, they used carbon labeling to show that the urea cycle was ‘reversed’ in FH-deficient cells.
Altered glucose metabolism of tumor cells was first noted by Otto Warburg in the 1920s, but the subsequent discovery of oncogenes and tumor suppressor genes drew the focus away from metabolic processes in tumor development. Now recent advances show that many oncogenes and tumor suppressor genes drive cancer by altering metabolic pathways, bringing the role of metabolism back into focus and suggesting new targets for therapy. Two such tumor suppressor genes are key components of the urea cycle: the enzymes succinate
dehydrogenase (SDH) and fumarate dehydrogenase (FH).
The urea cycle converts toxic ammonia to the nontoxic, excreted, urea through five steps that take place in the mitochondria and then cytosol. Step four is the cleavage of argininosuccinate into fumarate and arginine, which are then combined with water to produce urea and ornithine. Gottlieb shows that, unlike normal cells, the FH-deficient kidney cancer cells reverse this fourth step, producing argininosuccinate from fumarate and arginine. This may have a detoxifying effect by converting the huge excess of fumarate into the more useful argininosuccinate, which may fuel the cancer. Critically, this implies that FH-deficient kidney cancers, unlike normal kidney cells, rely on arginine in their diet. Indeed, depleting extracellular arginine from FH-deficient cells reduced their ability to grow, which may offer a route to new therapeutics. In addition, the identification of argininosuccinate as a product of FH deficiency could be used as a biomarker for FH-deficient kidney cancers, as it was present in mouse urine.
FH-deficient tumors are rare, but this study adds to the growing body of research on the interconnectedness of metabolic pathways and may help to highlight the role of cellular metabolism in cancer more generally. When deprived of a key enzyme, in this case FH, the cells are able to survive, indeed thrive, by turning metabolism on its head as essential co-factors are made by re-routed pathways. Once thought of as a dead-end subject, metabolism has been shown to be an intriguing hallmark of cancer and is now competitive area of research.