Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells
Open accessAbstract
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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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 Zheng et al., 2013
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Cites
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791 · see citing works
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., et al. (2011) · Nature · doi:10.1038/nature10350 · Cited by 1,683 · see citing works
Mutations in <i>SDHD</i> , a Mitochondrial Complex II Gene, in Hereditary Paraganglioma
Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., Mey, A. V. D., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., et al. (2000) · Science · doi:10.1126/science.287.5454.848 · Cited by 1,638 · see citing works
The Multiple Leiomyoma Consortium (2002) · Nature Genetics · doi:10.1038/ng849 · Cited by 1,635 · see citing works
Reductive carboxylation supports growth in tumour cells with defective mitochondria
Mullen, A. R., Wheaton, W. W., Jin, E. S., Chen, P.-H., Sullivan, L. B., Cheng, T., Yang, Y., Linehan, W. M., Chandel, N. S., & DeBerardinis, R. J. (2012) · Nature · doi:10.1038/nature10642 · Cited by 1,328 · see citing works
Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
Locasale, J. W., Grassian, A. R., Melman, T., Lyssiotis, C. A., Mattaini, K. R., Bass, A. J., Heffron, G., Metallo, C. M., Muranen, T., Sharfi, H., et al. (2011) · Nature Genetics · doi:10.1038/ng.890 · Cited by 1,120 · see citing works
Isaacs, J. S., Jung, Y. J., Mole, D. R., Lee, S., Torres-Cabala, C., Chung, Y.-L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.017 · Cited by 958 · see citing works
Pollard, P. J., Brière, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi227 · Cited by 865 · see citing works
The von Hippel–Lindau tumour suppressor protein: O2 sensing and cancer
Kaelin, W. G. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2502 · Cited by 731 · see citing works
Adam, J., Hatipoglu, E., O'Flaherty, L., Ternette, N., Sahgal, N., Lockstone, H., Baban, D., Nye, E., Stamp, G. W., Wolhuter, K., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.09.006 · Cited by 585 · see citing works
Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase
Frezza, C., Zheng, L., Folger, O., Rajagopalan, K. N., MacKenzie, E. D., Jerby, L., Micaroni, M., Chaneton, B., Adam, J., Hedley, A., et al. (2011) · Nature · doi:10.1038/nature10363 · Cited by 503 · see citing works
Self-citationOoi, A., Wong, J.-C., Petillo, D., Roossien, D., Perrier-Trudova, V., Whitten, D., Min, B. W. H., Tan, M.-H., Zhang, Z., Yang, X. J., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.08.024 · Cited by 401 · see citing works
Ireland, H., Kemp, R., Houghton, C. A., Howard, L., Clarke, A. R., Sansom, O. J., & Winton, D. J. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.03.020 · Cited by 343 · see citing works
Bardella, C., El‐Bahrawy, M., Frizzell, N., Adam, J., Ternette, N., Hatipoglu, E., Howarth, K., O'Flaherty, L., Roberts, I., Turner, G., et al. (2011) · The Journal of Pathology · doi:10.1002/path.2932 · Cited by 281 · see citing works
Requirement of argininosuccinate lyase for systemic nitric oxide production
Erez, A., Nagamani, S. C. S., Shchelochkov, O. A., Premkumar, M. H., Campeau, P. M., Chen, Y., Garg, H. K., Li, L., Mian, A., Bertin, T. K., et al. (2011) · Nature Medicine · doi:10.1038/nm.2544 · Cited by 233 · see citing works
Pollard, P. J., Spencer‐Dene, B., Shukla, D., Howarth, K. M., Nye, E. L., El-Bahrawy, M. A., Deheragoda, M. G., Kolatsi‐Joannou, M., McDonald, S. A. C., Martin, A., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.02.005 · Cited by 177 · see citing works
Inborn and acquired metabolic defects in cancer
Frezza, C., Pollard, P. J., & Gottlieb, E. (2011) · Journal of Molecular Medicine · doi:10.1007/s00109-011-0728-4 · Cited by 146 · see citing works
Self-citationYang, Y., Valera, V., Padilla‐Nash, H. M., Sourbier, C., Vocke, C. D., Vira, M. A., Abu-Asab, M. S., Bratslavsky, G., Tsokos, M., Merino, M. J., et al. (2009) · Cancer Genetics and Cytogenetics · doi:10.1016/j.cancergencyto.2009.08.018 · Cited by 139 · see citing works
Kinch, L. N., Grishin, N. V., & Brugarolas, J. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.10.005 · Cited by 106 · see citing works
Argininosuccinate lyase deficiency—Argininosuccinic aciduria and beyond
Erez, A., Nagamani, S. C. S., & Lee, B. (2011) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.30289 · Cited by 105 · see citing works
Kemp, R. (2004) · Nucleic Acids Research · doi:10.1093/nar/gnh090 · Cited by 85 · see citing works
Drug evaluation: ADI-PEG-20--a PEGylated arginine deiminase for arginine-auxotrophic cancers.
Shen, L., & Shen, W. (2006) · PubMed · Cited by 61 · see citing works
Sudarshan, S., Shanmugasundaram, K., Naylor, S. L., Lin, S., Livi, C. B., O’Neill, C. F., Parekh, D. J., Yeh, I., Sun, L., & Block, K. L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021037 · Cited by 52 · see citing works
Fumarate Hydratase Deficiency and Cancer: Activation of Hypoxia Signaling?
Ratcliffe, P. J. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.03.015 · Cited by 50 · see citing works
Cole, A. M., Ridgway, R. A., Derkits, S., Parry, L., Barker, N., Clevers, H. C., Clarke, A. R., & Sansom, O. J. (2010) · EMBO Molecular Medicine · doi:10.1002/emmm.201000101 · Cited by 35 · see citing works
K‐Ras‐Driven Pancreatic Cancer Mouse Model for Anticancer Inhibitor Analyses
Cook, N., Olive, K. P., Frese, K. K., & Tuveson, D. A. (2008) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(07)00406-5 · Cited by 28 · see citing works
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Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971 · see citing works
Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis
Cardaci, S., Zheng, L., MacKay, G., van den Broek, N. J. F., MacKenzie, E. D., Nixon, C., Stevenson, D., Tumanov, S., Bulusu, V., Kamphorst, J. J., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3233 · Cited by 286 · see citing works
Self-citationFumarate induces redox-dependent senescence by modifying glutathione metabolism
Zheng, L., Cardaci, S., Jerby, L., MacKenzie, E. D., Sciacovelli, M., Johnson, T. I., Gaude, E., King, A., Leach, J. D. G., Edrada-Ebel, R., et al. (2015) · Nature Communications · doi:10.1038/ncomms7001 · Cited by 281 · see citing works
Self-citationLussey-Lepoutre, C., Hollinshead, K. E. R., Ludwig, C., Menara, M., Morin, A., Castro-Vega, L.-J., Parker, S. J., Janin, M., Martinelli, C., Ottolenghi, C., et al. (2015) · Nature Communications · doi:10.1038/ncomms9784 · Cited by 227 · see citing works
Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges
Phillips, M. M., Sheaff, M. T., & Szlosarek, P. W. (2013) · Cancer Research and Treatment · doi:10.4143/crt.2013.45.4.251 · Cited by 229 · see citing works
Self-citationVazquez, A., Kamphorst, J. J., Markert, E. K., Schug, Z. T., Tardito, S., & Gottlieb, E. (2016) · Journal of Cell Science · doi:10.1242/jcs.181016 · Cited by 225 · see citing works
Self-citationMetabolic dysregulation in monogenic disorders and cancer — finding method in madness
Erez, A., & DeBerardinis, R. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3949 · Cited by 105 · see citing works
Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions
Guitart, A. V., Panagopoulou, T. I., Villacreces, A., Vukovic, M., Sepulveda, C., Allen, L., Carter, R. N., van de Lagemaat, L. N., Morgan, M., Giles, P., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20161087 · Cited by 86 · see citing works
- Authors
- Zheng, L., MacKenzie, E. D., Karim, S. A., Hedley, A., Blyth, K., Kalna, G., Watson, D. G., Szlosarek, P., Frezza, C., & Gottlieb, E.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- University of Strathclyde (GB)
- St Bartholomew's Hospital (GB)
- MRC Cancer Unit (GB)
- Corresponding author
- Frezza, Christian
- ORCID
- Venue
- Cancer & Metabolism
- Published
- 2013-03-21
- Volume
- 1
- Issue
- 1
- Pages
- 12-12
- ISSN
- 2049-3002 (ISSN-L)
- PMC
- PMC4108060
- OpenAlex
- W2135003533
- Cited by
- 103
- References
- 26
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 10 · 2023: 10 · 2022: 10 · 2021: 7 · 2020: 5 · 2019: 13 · 2018: 4 · 2017: 11 · 2016: 8 · 2015: 6 · 2014: 5 · 2013: 2
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Cancer & Metabolism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (acceptedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Cancer Research UK (11650)
- Medical Research Council (MC_UU_12022/6)
- National Cancer Institute
- 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 deficiency, argininosuccinate lyase, argininosuccinate, urea cycle, arginine auxotrophy, arginine deiminase, pegylated arginine deiminase, fumarate accumulation, hereditary leiomyomatosis and renal cell carcinoma, renal cell carcinoma, TCA cycle, metabolic biomarkers
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