A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia
Open accessAbstract
The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.
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High levels of fumarate resulting from FH deficiency drive argininosuccinate lyase and argininosuccinate synthase in a direction that consumes arginine, depleting intracellular arginine and making these cells arginine auxotrophs.
“The high levels of fumarate resulting from FH deficiency drives argininosuccinate lyase (ASL) and argininosuccinate synthase (ASS1) in a direction that consumes arginine (Figure 7). Depletion of intracellular arginine causes these cells to become arginine auxotrophs (Adam et al., 2013; Zheng et al., 2013), and therapies that deplete exogenous arginine (Table 1) may be effective in treating malign”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Adam et al., 2013
Targeting ACLY genetically or chemically prevents xenograft tumor formation and proliferation.
“ACLY activity is elevated in cancers (Migita et al., 2008), and targeting ACLY genetically or chemically prevents xenograft tumor formation and proliferation (Adam et al., 2013; Bauer et al., 2005; Hatzivassiliou et al., 2005; Migita et al., 2008).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Adam et al., 2013
FH and SDH mutations create truncal metabolic aberrations, induce permanent restructuring of the TCA cycle, and result in numerous metabolic liabilities in preclinical models.
“FH and SDH mutations also create truncal metabolic aberrations. These mutations induce permanent restructuring of the TCA cycle and result in numerous metabolic liabilities in preclinical models (106–108).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [108]
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- Authors
- Adam, J., Yang, M., Bauerschmidt, C., Kitagawa, M., O’Flaherty, L., Maheswaran, P., Özkan, G., Sahgal, N., Baban, D., Kato, K., Saito, K., Iino, K., Igarashi, K., Stratford, M., Pugh, C., Tennant, D. A., Ludwig, C., Davies, B., Ratcliffe, P. J., El-Bahrawy, M., Ashrafian, H., Soga, T., & Pollard, P. J.
- Affiliations
- University of Oxford (GB)
- Institute for Advanced Biosciences, Keio University (JP)
- Centre for Human Genetics (GB)
- University of Birmingham (GB)
- Hammersmith Hospital (GB)
- Keio University (JP)
- Corresponding author
- Pollard, Patrick J.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 3
- Issue
- 5
- Pages
- 1440-1448
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3675675
- OpenAlex
- W2051992679
- Cited by
- 97
- References
- 52
- Citations by year
- 2026: 9 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 7 · 2021: 10 · 2020: 8 · 2019: 7 · 2018: 10 · 2017: 9 · 2016: 6 · 2015: 5 · 2014: 6 · 2013: 4
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (WT091112MA, 090532, 090532/Z/09/Z, 090532/Z/09/)
- Cancer Research UK (13349, A14607, A12027, A13349)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- fumarate hydratase, urea cycle, arginine metabolism, renal neoplasia, renal cysts, TCA cycle, arginine deprivation, hereditary cancer, therapeutic target
- MeSH terms
- Animals, Arginine, Argininosuccinic Acid, Cell Line, Citric Acid Cycle, Fumarate Hydratase, Fumarates, Kidney, Kidney Neoplasms, Mice, Transgenic, Mitochondria, Mutation, Urea, Mice, Knockout, Protein Isoforms, Mice, Metabolome
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