Review Article | Published:

Rewiring urea cycle metabolism in cancer to support anabolism

Nature Reviews Cancervolume 18pages634645 (2018) | Download Citation

Abstract

Cancer cells reprogramme metabolism to maximize the use of nitrogen and carbon for the anabolic synthesis of macromolecules that are required during tumour proliferation and growth. To achieve this aim, one strategy is to reduce catabolism and nitrogen disposal. The urea cycle (UC) in the liver is the main metabolic pathway to convert excess nitrogen into disposable urea. Outside the liver, UC enzymes are differentially expressed, enabling the use of nitrogen for the synthesis of UC intermediates that are required to accommodate cellular needs. Interestingly, the expression of UC enzymes is altered in cancer, revealing a revolutionary mechanism to maximize nitrogen incorporation into biomass. In this Review, we discuss the metabolic benefits underlying UC deregulation in cancer and the relevance of these alterations for cancer diagnosis and therapy.

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References

  1. 1.

    Holmes, F. L. Hans Krebs and the discovery of the ornithine cycle. Fed. Proc. 39, 216–225 (1980).

  2. 2.

    Krebs, H. A. The history of the tricarboxylic acid cycle. Perspect. Biol. Med. 14, 154–170 (1970).

  3. 3.

    Krebs, H. A. The citric acid cycle: a reply to the criticisms of F. L. Breusch and of J. Thomas. Biochem. J. 34, 460–463 (1940).

  4. 4.

    Husson, A., Brasse-Lagnel, C., Fairand, A., Renouf, S. & Lavoinne, A. Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle. Eur. J. Biochem. 270, 1887–1899 (2003).

  5. 5.

    Erez, A., Nagamani, S. C. & Lee, B. Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. Am. J. Med. Genet. C Semin. Med. Genet. 157, 45–53 (2011).

  6. 6.

    Pesi, R., Balestri, F. & Ipata, P. L. Metabolic interaction between urea cycle and citric acid cycle shunt: a guided approach. Biochem. Mol. Biol. Educ. 46, 182–185 (2017).

  7. 7.

    Erez, A. Argininosuccinic aciduria: from a monogenic to a complex disorder. Genet. Med. 15, 251–257 (2013).

  8. 8.

    Ah Mew, N. et al. in GeneReviews (ed. Adam, M. P. et al.) (2017).

  9. 9.

    Spinelli, J. B. et al. Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science 358, 941–946 (2017). In this study, the authors demonstrate that nitrogenated waste can be efficiently incorporated into glutamate as a substrate for downstream reactions, to maximize nitrogen use by cancer cells.

  10. 10.

    Hensley, C. T., Wasti, A. T. & DeBerardinis, R. J. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J. Clin. Invest. 123, 3678–3684 (2013).

  11. 11.

    Yang, L., Venneti, S. & Nagrath, D. Glutaminolysis: a hallmark of cancer metabolism. Annu. Rev. Biomed. Eng. 19, 163–194 (2017).

  12. 12.

    Lu, P. et al. L-glutamine provides acid resistance for Escherichia coli through enzymatic release of ammonia. Cell Res. 23, 635–644 (2013).

  13. 13.

    Huang, W. et al. A proposed role for glutamine in cancer cell growth through acid resistance. Cell Res. 23, 724–727 (2013).

  14. 14.

    Bhutia, Y. D., Babu, E., Ramachandran, S. & Ganapathy, V. Amino acid transporters in cancer and their relevance to “glutamine addiction”: novel targets for the design of a new class of anticancer drugs. Cancer Res. 75, 1782–1788 (2015).

  15. 15.

    Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).

  16. 16.

    Davidson, S. M. et al. Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors. Nat. Med. 23, 235–241 (2017).

  17. 17.

    Hsieh, A. L., Walton, Z. E., Altman, B. J., Stine, Z. E. & Dang, C. V. MYC and metabolism on the path to cancer. Semin. Cell Dev. Biol. 43, 11–21 (2015).

  18. 18.

    Zhang, J., Pavlova, N. N. & Thompson, C. B. Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. EMBO J. 36, 1302–1315 (2017).

  19. 19.

    DeBerardinis, R. J. & Cheng, T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313–324 (2010).

  20. 20.

    Vander Heiden, M. G. Targeting cancer metabolism: a therapeutic window opens. Nat. Rev. Drug Discov. 10, 671–684 (2011).

  21. 21.

    Chen, Z., Tang, N., Wang, X. & Chen, Y. The activity of the carbamoyl phosphate synthase 1 promoter in human liver-derived cells is dependent on hepatocyte nuclear factor 3-beta. J. Cell. Mol. Med. 21, 2036–2045 (2017).

  22. 22.

    Nakagawa, T., Lomb, D. J., Haigis, M. C. & Guarente, L. SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137, 560–570 (2009).

  23. 23.

    Tan, M. et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab. 19, 605–617 (2014).

  24. 24.

    Moreno-Morcillo, M. et al. Structural insight into the core of CAD, the multifunctional protein leading de novo pyrimidine biosynthesis. Structure 25, 912–923 (2017).

  25. 25.

    Kim, J. et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 546, 168–172 (2017).

  26. 26.

    Celiktas, M. et al. Role of CPS1 in cell growth, metabolism and prognosis in LKB1-inactivated lung adenocarcinoma. J. Natl Cancer Inst. 109, 1–9 (2017). Refs 25 and 26 demonstrate that loss of the tumour suppressor LKB1 results in the accumulation of the enzyme CPS1, hence perturbing the UC and increasing the availability of carbamoylphosphate for pyrimidine synthesis.

  27. 27.

    Lee, Y. Y. et al. Overexpression of CPS1 is an independent negative prognosticator in rectal cancers receiving concurrent chemoradiotherapy. Tumour Biol. 35, 11097–11105 (2014).

  28. 28.

    May, D. et al. Investigating neoplastic progression of ulcerative colitis with label-free comparative proteomics. J. Proteome Res. 10, 200–209 (2011).

  29. 29.

    Palaniappan, A., Ramar, K. & Ramalingam, S. Computational identification of novel stage-specific biomarkers in colorectal cancer progression. PLOS ONE 11, e0156665 (2016).

  30. 30.

    Ma, S. L., Li, A. J., Hu, Z. Y., Shang, F. S. & Wu, M. C. Coexpression of the carbamoylphosphate synthase 1 gene and its long noncoding RNA correlates with poor prognosis of patients with intrahepatic cholangiocarcinoma. Mol. Med. Rep. 12, 7915–7926 (2015).

  31. 31.

    Milinkovic, V. et al. Identification of novel genetic alterations in samples of malignant glioma patients. PLOS ONE 8, e82108 (2013).

  32. 32.

    Cardona, D. M., Zhang, X. & Liu, C. Loss of carbamoyl phosphate synthetase I in small-intestinal adenocarcinoma. Am. J. Clin. Pathol. 132, 877–882 (2009).

  33. 33.

    Liu, H., Dong, H., Robertson, K. & Liu, C. DNA methylation suppresses expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) in human hepatocellular carcinoma. Am. J. Pathol. 178, 652–661 (2011).

  34. 34.

    Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169, 1327–1341 (2017).

  35. 35.

    Su, Y. et al. Optimizing combination of liver-enriched transcription factors and nuclear receptors simultaneously favors ammonia and drug metabolism in liver cells. Exp. Cell Res. 362, 504–514 (2018).

  36. 36.

    Li, L. et al. PGC-1alpha promotes ureagenesis in mouse periportal hepatocytes through SIRT3 and SIRT5 in response to glucagon. Sci. Rep. 6, 24156 (2016).

  37. 37.

    Gao, Y. et al. Quantitative proteomics by SWATH-MS reveals sophisticated metabolic reprogramming in hepatocellular carcinoma tissues. Sci. Rep. 7, 45913 (2017).

  38. 38.

    Vardon, A. et al. Arginine auxotrophic gene signature in paediatric sarcomas and brain tumours provides a viable target for arginine depletion therapies. Oncotarget 8, 63506–63517 (2017).

  39. 39.

    De Santo, C. et al. The arginine metabolome in acute lymphoblastic leukemia can be targeted by the pegylated-recombinant arginase I BCT-100. Int. J. Cancer 142, 1490–1502 (2018).

  40. 40.

    Gui, D. Y. et al. Environment dictates dependence on mitochondrial complex I for NAD+ and aspartate production and determines cancer cell sensitivity to metformin. Cell Metab. 24, 716–727 (2016).

  41. 41.

    Patel, D. et al. Aspartate rescues S-phase arrest caused by suppression of glutamine utilization in KRas-driven cancer cells. J. Biol. Chem. 291, 9322–9329 (2016).

  42. 42.

    Sullivan, L. B. et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162, 552–563 (2015). This study demonstrates that electron acceptors that are essential for mitochondrial respiration sustain aspartate synthesis. In turn, asparte production fuels pyrimidine biosynthesis for cell proliferation.

  43. 43.

    Rabinovich, S. et al. Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. Nature 527, 379–383 (2015). Key genetic analysis of ASS1 loss in cancer detailing roles in tumor propagation via increased pyrimidine synthesis and mTOR activation with consequent therapeutic implications.

  44. 44.

    Birsoy, K. et al. An Essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162, 540–551 (2015). This study shows that reverse GOT1 activity or pyruvate supplementation produces cytoplasmic aspartate and sustains nucleotide synthesis in conditions in which mitochondrial aspartate production is impaired.

  45. 45.

    Garcia-Bermudez, J. et al. Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. Nat. Cell Biol. 20, 775–781 (2018).

  46. 46.

    Fu, A. & Danial, N. N. Grasping for aspartate in tumour metabolism. Nat. Cell Biol. 20, 738–739 (2018).

  47. 47.

    Cardaci, S. et al. Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat. Cell Biol. 17, 1317–1326 (2015).

  48. 48.

    Sullivan, L. B. et al. Aspartate is an endogenous metabolic limitation for tumour growth. Nat. Cell Biol. 20, 782–788 (2018). This study shows that the reduced capacity of cancer cells to uptake extracellular aspartate (as opposed to the high uptake rate of asparagine) results in the dependence on endogenous production of aspartate to support nucleotide synthesis.

  49. 49.

    Dong, H. et al. Digital karyotyping reveals probable target genes at 7q21.3 locus in hepatocellular carcinoma. BMC Med. Genom. 4, 60 (2011).

  50. 50.

    Amoedo, N. D. et al. AGC1/2, the mitochondrial aspartate-glutamate carriers. Biochim. Biophys. Acta 1863, 2394–2412 (2016).

  51. 51.

    Miyo, M. et al. Metabolic adaptation to nutritional stress in human colorectal cancer. Sci. Rep. 6, 38415 (2016).

  52. 52.

    Miyamoto, T. et al. Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53. Sci. Adv. 3, e1603204 (2017).

  53. 53.

    Tsai, W. B. et al. Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc/HIF-1alpha/Sp4. Mol. Cancer Ther. 8, 3223–3233 (2009). This study details a common resistance pathway to arginine deprivation via ASS1 re-expression in cancer involving displacement of HIF1α by MYC.

  54. 54.

    Long, Y. et al. Cisplatin-induced synthetic lethality to arginine-starvation therapy by transcriptional suppression of ASS1 is regulated by DEC1, HIF-1alpha, and c-Myc transcription network and is independent of ASS1 promoter DNA methylation. Oncotarget 7, 82658–82670 (2016).

  55. 55.

    Lin, R. et al. CLOCK acetylates ASS1 to drive circadian rhythm of ureagenesis. Mol. Cell 68, 198–209 (2017).

  56. 56.

    Sahar, S. & Sassone-Corsi, P. Metabolism and cancer: the circadian clock connection. Nat. Rev. Cancer 9, 886–896 (2009).

  57. 57.

    Liu, Q. et al. Reduced expression of argininosuccinate synthetase 1 has a negative prognostic impact in patients with pancreatic ductal adenocarcinoma. PLOS ONE 12, e0171985 (2017).

  58. 58.

    Sahu, D. et al. Argininosuccinate synthetase 1 loss in invasive bladder cancer regulates survival through general control nonderepressible 2 kinase-mediated eukaryotic initiation factor 2alpha activity and is targetable by pegylated arginine deiminase. Am. J. Pathol. https://doi.org/10.1016/j.ajpath.2016.09.004 (2016).

  59. 59.

    Kim, Y. et al. Reduced argininosuccinate synthetase expression in refractory sarcomas: impacts on therapeutic potential and drug resistance. Oncotarget 7, 70832–70844 (2016).

  60. 60.

    Wu, L. et al. Expression of argininosuccinate synthetase in patients with hepatocellular carcinoma. J. Gastroenterol. Hepatol. 28, 365–368 (2013).

  61. 61.

    Camacho, J. A. et al. Hyperornithinaemia–hyperammonaemia–homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat. Genet. 22, 151–158 (1999).

  62. 62.

    Szlosarek, P. W. et al. Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial. JAMA Oncol. 3, 58–66 (2017).

  63. 63.

    Zheng, L. et al. Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells. Cancer Metab. 1, 12 (2013).

  64. 64.

    Kobayashi, E. et al. Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma. Mol. Cancer Ther. 9, 535–544 (2010). Important study describing enhanced metastasis in ASS1-deficient osteosarcoma.

  65. 65.

    Syed, N. et al. Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma. Cell Death Dis. 4, e458 (2013).

  66. 66.

    Delage, B. et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int. J. Cancer 126, 2762–2772 (2010).

  67. 67.

    Bateman, L. A. et al. Argininosuccinate synthase 1 is a metabolic regulator of colorectal cancer pathogenicity. ACS Chem. Biol. 12, 905–911 (2017).

  68. 68.

    Shan, Y. S. et al. Argininosuccinate synthetase 1 suppression and arginine restriction inhibit cell migration in gastric cancer cell lines. Sci. Rep. 5, 9783 (2015).

  69. 69.

    Tsai, C. Y. et al. Argininosuccinate synthetase 1 contributes to gastric cancer invasion and progression by modulating autophagy. FASEB J. 32, 2601–2614 (2018).

  70. 70.

    Yuan, J., Zhang, F. & Niu, R. Multiple regulation pathways and pivotal biological functions of STAT3 in cancer. Sci. Rep. 5, 17663 (2015).

  71. 71.

    Yoon, S. et al. NF-kappaB and STAT3 cooperatively induce IL6 in starved cancer cells. Oncogene 31, 3467–3481 (2012).

  72. 72.

    Madiraju, A. K. et al. Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism. Proc. Natl Acad. Sci. USA 113, E3423–E3430 (2016).

  73. 73.

    Amara, S. et al. Critical role of SIK3 in mediating high salt and IL-17 synergy leading to breast cancer cell proliferation. PLOS ONE 12, e0180097 (2017).

  74. 74.

    Adam, J. et al. A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia. Cell Rep. 3, 1440–1448 (2013). Refs 63 and 74 highlight the important connection between the UC and the TCA cycle that can work in both direcions and contribute to oncogenesis.

  75. 75.

    Huang, H. L. et al. Silencing of argininosuccinate lyase inhibits colorectal cancer formation. Oncol. Rep. 37, 163–170 (2017).

  76. 76.

    Huang, H. L. et al. Argininosuccinate lyase is a potential therapeutic target in breast cancer. Oncol. Rep. 34, 3131–3139 (2015).

  77. 77.

    Huang, H. L. et al. Attenuation of argininosuccinate lyase inhibits cancer growth via cyclin A2 and nitric oxide. Mol. Cancer Ther. 12, 2505–2516 (2013).

  78. 78.

    Erez, A. et al. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat. Med. 17, 1619–1626 (2011).

  79. 79.

    Burke, A. J., Sullivan, F. J., Giles, F. J. & Glynn, S. A. The yin and yang of nitric oxide in cancer progression. Carcinogenesis 34, 503–512 (2013).

  80. 80.

    Stettner, N. et al. Induction of nitric-oxide metabolism in enterocytes alleviates colitis and inflammation-associated colon cancer. Cell Rep. 23, 1962–1976 (2018).

  81. 81.

    Dai, Z. et al. Nitric oxide and energy metabolism in mammals. Biofactors 39, 383–391 (2013).

  82. 82.

    Lira, V. A. et al. Nitric oxide and AMPK cooperatively regulate PGC-1 in skeletal muscle cells. J. Physiol. 588, 3551–3566 (2010).

  83. 83.

    Cho, D. H. et al. S-Nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324, 102–105 (2009).

  84. 84.

    Kerins, M. J. et al. Fumarate mediates a chronic proliferative signal in fumarate hydratase-inactivated cancer cells by increasing transcription and translation of ferritin genes. Mol. Cell. Biol. https://doi.org/10.1128/MCB.00079-17 (2017).

  85. 85.

    Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016).

  86. 86.

    Porcelli, V., Fiermonte, G., Longo, A. & Palmieri, F. The human gene SLC25A29, of solute carrier family 25, encodes a mitochondrial transporter of basic amino acids. J. Biol. Chem. 289, 13374–13384 (2014).

  87. 87.

    Zhang, H. et al. Elevated mitochondrial SLC25A29 in cancer modulates metabolic status by increasing mitochondria-derived nitric oxide. Oncogene 37, 2545–2558 (2018).

  88. 88.

    Morrissey, J., McCracken, R., Ishidoya, S. & Klahr, S. Partial cloning and characterization of an arginine decarboxylase in the kidney. Kidney Int. 47, 1458–1461 (1995).

  89. 89.

    Galea, E., Regunathan, S., Eliopoulos, V., Feinstein, D. L. & Reis, D. J. Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem. J. 316, 247–249 (1996).

  90. 90.

    Satriano, J. et al. Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels. J. Biol. Chem. 273, 15313–15316 (1998).

  91. 91.

    Vargiu, C. et al. Agmatine modulates polyamine content in hepatocytes by inducing spermidine/spermine acetyltransferase. Eur. J. Biochem. 259, 933–938 (1999).

  92. 92.

    Wyant, G. A. et al. mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient. Cell 171, 642–654 (2017).

  93. 93.

    Geiger, R. et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842 (2016).

  94. 94.

    Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011).

  95. 95.

    Xiao, M. et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).

  96. 96.

    Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011).

  97. 97.

    Nowicki, S. & Gottlieb, E. Oncometabolites: tailoring our genes. FEBS J. 282, 2796–2805 (2015).

  98. 98.

    Levillain, O., Balvay, S. & Peyrol, S. Localization and differential expression of arginase II in the kidney of male and female mice. Pflugers Arch. 449, 491–503 (2005).

  99. 99.

    Pandey, D. et al. Hypoxia triggers SENP1 (sentrin-specific protease 1) modulation of KLF15 (Kruppel-like factor 15) and transcriptional regulation of Arg2 (Arginase 2) in pulmonary endothelium. Arterioscler. Thromb. Vasc. Biol. 38, 913–926 (2018).

  100. 100.

    Kurzejamska, E. et al. C/EBPbeta expression is an independent predictor of overall survival in breast cancer patients by MHCII/CD4-dependent mechanism of metastasis formation. Oncogenesis 3, e125 (2014).

  101. 101.

    Ray, S. & Pollard, J. W. KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing. Proc. Natl Acad. Sci. USA 109, E1334–E1343 (2012).

  102. 102.

    Chaerkady, R. et al. A quantitative proteomic approach for identification of potential biomarkers in hepatocellular carcinoma. J. Proteome Res. 7, 4289–4298 (2008).

  103. 103.

    Zaytouni, T. et al. Critical role for arginase 2 in obesity-associated pancreatic cancer. Nat. Commun. 8, 242 (2017).

  104. 104.

    Secondini, C. et al. Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade. Oncoimmunology 6, e1316437 (2017).

  105. 105.

    Ochocki, J. D. et al. Arginase 2 suppresses renal carcinoma progression via biosynthetic cofactor pyridoxal phosphate depletion and increased polyamine toxicity. Cell Metab. 27, 1263–1280 (2018).

  106. 106.

    Erbas, H., Bal, O. & Cakir, E. Effect of rosuvastatin on arginase enzyme activity and polyamine production in experimental breast cancer. Balkan Med. J. 32, 89–95 (2015).

  107. 107.

    Singh, R. et al. Proteomic identification of mitochondrial targets of arginase in human breast cancer. PLOS ONE 8, e79242 (2013).

  108. 108.

    Cervelli, M., Pietropaoli, S., Signore, F., Amendola, R. & Mariottini, P. Polyamines metabolism and breast cancer: state of the art and perspectives. Breast Cancer Res. Treat. 148, 233–248 (2014).

  109. 109.

    Arruabarrena-Aristorena, A., Zabala-Letona, A. & Carracedo, A. Oil for the cancer engine: the cross-talk between oncogenic signaling and polyamine metabolism. Sci. Adv. 4, eaar2606 (2018).

  110. 110.

    Bello-Fernandez, C., Packham, G. & Cleveland, J. L. The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc. Natl Acad. Sci. USA 90, 7804–7808 (1993).

  111. 111.

    Camacho, J. A., Rioseco-Camacho, N., Andrade, D., Porter, J. & Kong, J. Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder. Mol. Genet. Metab. 79, 257–271 (2003).

  112. 112.

    Lytovchenko, O. & Kunji, E. R. S. Expression and putative role of mitochondrial transport proteins in cancer. Biochim. Biophys. Acta 1858, 641–654 (2017).

  113. 113.

    Sotgia, F. et al. Mitochondria “fuel” breast cancer metabolism: fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells. Cell Cycle 11, 4390–4401 (2012).

  114. 114.

    Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

  115. 115.

    Sharda, D. R. et al. Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase. J. Immunol. 187, 2181–2192 (2011).

  116. 116.

    Phillips, M. M., Sheaff, M. & Szlosarek, P. W. Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges. Cancer Res. Treat. 45, 251–262 (2013).

  117. 117.

    Patil, M. D., Bhaumik, J., Babykutty, S., Banerjee, U. C. & Fukumura, D. Arginine dependence of tumor cells: targeting a chink in cancer’s armor. Oncogene 35, 4957–4972 (2016).

  118. 118.

    Izzo, F. et al. Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies. J. Clin. Oncol. 22, 1815–1822 (2004).

  119. 119.

    Ascierto, P. A. et al. Pegylated arginine deiminase treatment of patients with metastatic melanoma: results from phase I and II studies. J. Clin. Oncol. 23, 7660–7668 (2005).

  120. 120.

    Szlosarek, P. W. et al. In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion. Clin. Cancer Res. 12, 7126–7131 (2006). Key study annotating methylation-dependent silencing of ASS1 as a mechanism for arginine auxotrphy in human cancer.

  121. 121.

    Tsai, H. J. et al. A Phase II study of arginine deiminase (ADI-PEG20) in relapsed/refractory or poor-risk acute myeloid leukemia patients. Sci. Rep. 7, 11253 (2017).

  122. 122.

    Delage, B. et al. Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis. Cell Death Dis. 3, e342 (2012).

  123. 123.

    Cheng, P. N. et al. Pegylated recombinant human arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion. Cancer Res. 67, 309–317 (2007).

  124. 124.

    Lam, T. L. et al. Recombinant human arginase inhibits the in vitro and in vivo proliferation of human melanoma by inducing cell cycle arrest and apoptosis. Pigment Cell Melanoma Res. 24, 366–376 (2011).

  125. 125.

    Morrow, K. et al. Anti-leukemic mechanisms of pegylated arginase I in acute lymphoblastic T cell leukemia. Leukemia 27, 569–577 (2013).

  126. 126.

    Rodriguez, P. C. et al. Regulation of T cell receptor CD3zeta chain expression by L-arginine. J. Biol. Chem. 277, 21123–21129 (2002).

  127. 127.

    Zea, A. H. et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 65, 3044–3048 (2005).

  128. 128.

    Agrawal, V. et al. Cytotoxicity of human recombinant arginase I (Co)-PEG5000 in the presence of supplemental L-citrulline is dependent on decreased argininosuccinate synthetase expression in human cells. Anticancer Drugs 23, 51–64 (2012).

  129. 129.

    Mauldin, J. P. et al. Recombinant human arginase toxicity in mice is reduced by citrulline supplementation. Transl Oncol. 5, 26–31 (2012).

  130. 130.

    Yau, T. et al. A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma. Invest. New Drugs 31, 99–107 (2013).

  131. 131.

    Yau, T. et al. Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma. Invest. New Drugs 33, 496–504 (2015).

  132. 132.

    Drew, W. et al. in Proc. AACR Annu. Meet. 2018 (Chicago, USA, 2018).

  133. 133.

    Allen, M. D. et al. Prognostic and therapeutic impact of argininosuccinate synthetase 1 control in bladder cancer as monitored longitudinally by PET imaging. Cancer Res. 74, 896–907 (2014). Important preclinical study detailing pharmacological effects of arginine deprivation with ADI-PEG20 on de novo pyrimidine synthesis and salvage in arginine auxotrophic tumours.

  134. 134.

    Beddowes, E. et al. Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers. J. Clin. Oncol. 35, 1778–1785 (2017). Clinical study of ADI-PEG20 combined with antifolate-based chemotherapy showing a 100% disease control rate in chemorefractory ASS1-deficient thoracic cancers.

  135. 135.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02709512?cond=NCT02709512&rank=1 (2018).

  136. 136.

    Harding, J. J. et al. A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies. Cancer Chemother. Pharmacol. https://doi.org/10.1007/s00280-018-3635-3 (2018).

  137. 137.

    Glazer, E. S. et al. Phase II study of pegylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma. J. Clin. Oncol. 28, 2220–2226 (2010).

  138. 138.

    Yang, T. S. et al. A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br. J. Cancer 103, 954–960 (2010).

  139. 139.

    Bean, G. R. et al. A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas. Cell Death Dis. 7, e2406 (2016). Proof-of-principle human ASS1-negative sarcoma xenograft study showing potentiation of ADI-PEG20 by choloroquine as a modulator of autophagy.

  140. 140.

    Long, Y. et al. Arginine deiminase resistance in melanoma cells is associated with metabolic reprogramming, glucose dependence and glutamine addiction. Mol. Cancer Ther. 12, 2581–2590 (2013).

  141. 141.

    Tsai, W. B. et al. Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells. Cancer Res. 72, 2622–2633 (2012).

  142. 142.

    Lam, S. K. et al. Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models. Oncol. Rep. https://doi.org/10.3892/or.2018.6598 (2018).

  143. 143.

    Locke, M. et al. Inhibition of the polyamine synthesis pathway is synthetically lethal with loss of argininosuccinate synthase 1. Cell Rep. 16, 1604–1613 (2016).

  144. 144.

    Lee, J. S. et al. Urea cycle dysregulation generates clinically relevant genomic and biochemical signatures. Cell. https://doi.org/10.1016/j.cell.2018.07.019 (2018).

  145. 145.

    Brin, E. et al. PEGylated arginine deiminase can modulate tumor immune microenvironment by affecting immune checkpoint expression, decreasing regulatory T cell accumulation and inducing tumor T cell infiltration. Oncotarget 8, 58948–58963 (2017).

  146. 146.

    Werner, A. et al. Reconstitution of T cell proliferation under arginine limitation: activated human T cells take up citrulline via L-type amino acid transporter 1 and use it to regenerate arginine after induction of argininosuccinate synthase expression. Front. Immunol. 8, 864 (2017).

  147. 147.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03498222?cond=NCT03498222&rank=1 (2018).

  148. 148.

    Stone, E. M. et al. Replacing Mn(2+) with Co(2+) in human arginase i enhances cytotoxicity toward l-arginine auxotrophic cancer cell lines. ACS Chem. Biol. 5, 333–342 (2010).

  149. 149.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03371979?cond=NCT03371979&rank=1 (2018).

  150. 150.

    Davidson, J. N., Chen, K. C., Jamison, R. S., Musmanno, L. A. & Kern, C. B. The evolutionary history of the first three enzymes in pyrimidine biosynthesis. Bioessays 15, 157–164 (1993).

  151. 151.

    Berg, J. M., T. J. & Stryer, L. Biochemistry 5th edn (W H Freeman, 2002).

  152. 152.

    Allegra, C. J., Hoang, K., Yeh, G. C., Drake, J. C. & Baram, J. Evidence for direct inhibition of de novo purine synthesis in human MCF-7 breast cells as a principal mode of metabolic inhibition by methotrexate. J. Biol. Chem. 262, 13520–13526 (1987).

  153. 153.

    Fearon, K. C., Glass, D. J. & Guttridge, D. C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 16, 153–166 (2012).

  154. 154.

    Vynnytska, B. O., Mayevska, O. M., Kurlishchuk, Y. V., Bobak, Y. P. & Stasyk, O. V. Canavanine augments proapoptotic effects of arginine deprivation in cultured human cancer cells. Anticancer Drugs 22, 148–157 (2011).

  155. 155.

    Gong, H. et al. Arginine deiminase and other antiangiogenic agents inhibit unfavorable neuroblastoma growth: potentiation by irradiation. Int. J. Cancer 106, 723–728 (2003).

  156. 156.

    Hinrichs, C. N. et al. Arginine deprivation therapy: putative strategy to eradicate glioblastoma cells by radiosensitization. Mol. Cancer Ther. 17, 393–406 (2018).

  157. 157.

    Wangpaichitr, M. et al. Combination of arginine deprivation with TRAIL treatment as a targeted-therapy for mesothelioma. Anticancer Res. 34, 6991–6999 (2014).

  158. 158.

    Abou-Alfa, G. et al. Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma. Ann. Oncol. 29, 1402–1408 (2018).

  159. 159.

    Ott, P. A. et al. Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma. Invest. New Drugs 31, 425–434 (2013).

  160. 160.

    Tomlinson, B. K. et al. Phase I trial of arginine deprivation therapy with ADI-PEG 20 plus docetaxel in patients with advanced malignant solid tumors. Clin. Cancer Res. 21, 2480–2486 (2015).

  161. 161.

    Lowery, M. A. et al. A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma. Cancer 123, 4556–4565 (2017).

  162. 162.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01266018?cond=NCT01266018&rank=1 (2017).

  163. 163.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01948843?cond=NCT01948843&rank=1 (2016).

  164. 164.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01665183?cond=NCT01665183&rank=1 (2016).

  165. 165.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03254732?cond=NCT03254732&rank=1 (2018).

  166. 166.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03449901?cond=NCT03449901&rank=1 (2018).

  167. 167.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02732184?cond=NCT02732184&rank=1 (2018).

  168. 168.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02561234?cond=NCT02561234&rank=1 (2018).

  169. 169.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02899286?cond=NCT02899286&rank=1 (2017).

  170. 170.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02089633?cond=NCT02089633&rank=1 (2017).

  171. 171.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03455140?cond=NCT03455140&rank=1 (2018).

  172. 172.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03314935?cond=NCT03314935&rank=1 (2018).

  173. 173.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02903914?cond=NCT02903914&rank=1 (2018).

  174. 174.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03361228?cond=NCT03361228&rank=1 (2018).

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Acknowledgements

A.E. is the incumbent of the Leah Omenn Career Development Chair and is supported by research grants from the European Research Program (CIG618113 and ERC614204), the Israel Science Foundation (1343/13 and 1952/13) and a Minerva grant award (711730). A.E. received additional support from the Adelis Foundation, the Henry S. and Anne S. Reich Research Fund, the Dukler Fund for Cancer Research, the Paul Sparr Foundation, the Saul and Theresa Esman Foundation, Joseph Piko Baruch and the estate of Fannie Sherr. R.K. is supported by the Rising Tide Foundation (721543). P.S. is supported by the Higher Education Funding Council for England and research grants from Cancer Research UK, British Lung Foundation, Barts Charity and Polaris Pharma. The work of A.C. is supported by the Basque Department of Industry, Tourism and Trade (Etortek) and the Department of Education (IKERTALDE IT1106-16), the Spanish Association Against Cancer (AECC, IDEAS175CARR), the Banco Bilbao Vizcaya Argentaria (BBVA) foundation, the Ministerio de Economía y Competitividad (MINECO) (SAF2016-79381-R (Fondo Europeo de Desarrollo Regional (FEDER)/European Union (EU)); Severo Ochoa Excellence Accreditation SEV-2016-0644) and the European Commission (European Research Council (ERC) Starting Grant 336343, ERC Proof of Concept 754627, H2020-MSCA-ITN 721532). CIBERONC was co-funded with FEDER funds.

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Nature Reviews Cancer thanks C. Frezza and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Affiliations

  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    • Rom Keshet
    •  & Ayelet Erez
  2. Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK

    • Peter Szlosarek
  3. Barts Health NHS Trust, St Bartholomew’s Hospital, London, UK

    • Peter Szlosarek
  4. CIC bioGUNE, Bizkaia, Spain

    • Arkaitz Carracedo
  5. CIBERONC, Instituto de Salud Carlos III, Madrid, Spain

    • Arkaitz Carracedo
  6. Ikerbasque, Basque Foundation for Science, Bilbao, Spain

    • Arkaitz Carracedo
  7. Biochemistry and Molecular Biology Department, University of the Basque Country, Bilbao, Spain

    • Arkaitz Carracedo

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Contributions

A.E., P.S. and A.C. researched data for the article, substantially contributed to the discussion of content, contributed to writing the article and generating the figures and reviewed and edited the manuscript before submission. R.K. researched data for the article and contributed to writing the article and generating the figures.

Competing interests

P.S. receives research funding support and is an investigator on clinical trials of PEGylated arginine deaminase (ADI-PEG20) from Polaris Pharma.

Corresponding author

Correspondence to Ayelet Erez.

Supplementary information

Glossary

Anaplerosis

The process of replenishing depleted metabolic cycle or pathway intermediates.

Aspartate transcarbamylase

An enzyme that catalyses the formation of carbamoyl aspartic acid and inorganic phosphate from aspartate and carbamoyl phosphate (CP), which is the first step in pyrimidine synthesis.

Dihydroorotase

An enzyme that catalyses the formation of 4,5-dihydroorotic acid from carbamoyl aspartic acid during pyrimidine synthesis.

Pyrimidine

An aromatic ring composed of two nitrogen atoms and four carbon atoms, from which derive the three nitrogenous bases thymine, uracil and cytosine.

Compartmentalization

The restriction of a cellular component or process within a defined cellular compartment, such as the cytosol or a specific organelle.

Pyruvate carboxylase

A mitochondrial enzyme that catalyses the formation of oxaloacetate from pyruvate. The reaction is irreversible. Oxaloacetate can replenish the tricarboxylic acid cycle or be used for gluconeogenesis.

Fumarate hydratase

(FH). An enzyme that catalyses the hydration of fumarate to malate in the tricarboxylic acid cycle (mitochondrial isoform) or as a reaction contributing to fumarate and amino acid metabolism in the cytosol (cytosolic isoform). The reaction is reversible.

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DOI

https://doi.org/10.1038/s41568-018-0054-z

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