Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The metabolic fate of acetate in cancer

Nature Reviews Cancer volume 16, pages 708–717 (2016)Cite this article

Subjects

Key Points

  • Acetate can be used by tumour cells as an important bioenergetic fuel or as a nutritional source to support lipid biosynthesis.

  • Acetate can be a precursor for acetylation of histones and other proteins and hence can serve as an epigenetic and post-translational modifier.

  • Despite the low circulating concentration of acetate, acetate may still exert its effects through intra- and intercellular recycling of acetate molecules within the tumour microenvironment or at sites with high local acetate concentrations.

  • Acetyl-CoA synthetase 2 (ACSS2) is emerging as an important enzyme in the growth of many different types of cancers and is induced by cancer cells in response to nutrient stress conditions. Targeting ACSS2 may prove to be a powerful therapeutic modality.

  • ACSS2 is highly upregulated in multiple cancer types and may be a useful biomarker for anti-ACSS2 therapies.

  • [11C]acetate has demonstrated excellent potential as an alternative positron emission tomography imaging probe for cancer. More studies on why some but not other tumours are [11C]acetate avid, and correlating these data with the expression of acetyl-CoA synthetases will aid in deciphering the exact manner by which acetate metabolism supports tumour growth and help in stratifying patients for future anti-ACSS2 therapy.

Abstract

Recent high-profile reports have reignited an interest in acetate metabolism in cancer. Acetyl-CoA synthetases that catalyse the conversion of acetate to acetyl-CoA have now been implicated in the growth of hepatocellular carcinoma, glioblastoma, breast cancer and prostate cancer. In this Review, we discuss how acetate functions as a nutritional source for tumours and as a regulator of cancer cell stress, and how preventing its (re)capture by cancer cells may provide an opportunity for therapeutic intervention.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sources and production sites of acetate in the human body.
Figure 2: Production of acetate by the commensal microbiota and the subsequent uptake by colonic epithelial cells.
Figure 3: Intracellular acetate metabolism and the flow of acetate carbons.

Similar content being viewed by others

References

  1. Medes, G., Friedmann, B. & Weinhouse, S. Fatty acid metabolism. VIII. Acetate metabolism in vitro during hepatocarcinogenesis by p-dimethylaminoazobenzene. Cancer Res. 16, 57–62 (1956).

    CAS  PubMed  Google Scholar 

  2. Medes, G. & Weinhouse, S. Metabolism of neoplastic tissue. XIII. Substrate competition in fatty acid oxidation in ascites tumor cells. Cancer Res. 18, 352–359 (1958).

    CAS  PubMed  Google Scholar 

  3. Medes, G., Paden, G. & Weinhouse, S. Metabolism of neoplastic tissues. XI. Absorption and oxidation of dietary fatty acids by implanted tumors. Cancer Res. 17, 127–133 (1957).

    CAS  PubMed  Google Scholar 

  4. Thomlinson, R. H. & Gray, L. H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer 9, 539–549 (1955).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nath, A. & Chan, C. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers. Sci. Rep. 6, 18669 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Azzi, S., Hebda, J. K. & Gavard, J. Vascular permeability and drug delivery in cancers. Front. Oncol. 3, 211 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Joint FAO/WHO Codex Alimentarius Commission. Codex general standard for food additives http://www.fao.org/fao-who-codexalimentarius/download/standards/4/CXS_192_2015e.pdf (Joint FAO/WHO Codex Alimentarius Commission, 2015).

  10. Suematsu, N. & Isohashi, F. Molecular cloning and functional expression of human cytosolic acetyl-CoA hydrolase. Acta Biochim. Pol. 53, 553–561 (2006).

    CAS  PubMed  Google Scholar 

  11. Horibata, Y., Ando, H., Itoh, M. & Sugimoto, H. Enzymatic and transcriptional regulation of the cytoplasmic acetyl-CoA hydrolase ACOT12. J. Lipid Res. 54, 2049–2059 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Scheppach, W., Pomare, E. W., Elia, M. & Cummings, J. H. The contribution of the large intestine to blood acetate in man. Clin. Sci. (Lond.) 80, 177–182 (1991).

    Article  CAS  Google Scholar 

  13. Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12, 661–672 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Cummings, J. H., Pomare, E. W., Branch, W. J., Naylor, C. P. & Macfarlane, G. T. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28, 1221–1227 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schuchmann, K. & Muller, V. Autotrophy at the thermodynamic limit of life: a model for energy conservation in acetogenic bacteria. Nat. Rev. Microbiol. 12, 809–821 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Rey, F. E. et al. Dissecting the in vivo metabolic potential of two human gut acetogens. J. Biol. Chem. 285, 22082–22090 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Donohoe, D. R. et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13, 517–526 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bloemen, J. G. et al. Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clin. Nutr. 28, 657–661 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Rocco, A., Compare, D., Angrisani, D., Sanduzzi Zamparelli, M. & Nardone, G. Alcoholic disease: liver and beyond. World J. Gastroenterol. 20, 14652–14659 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nuutinen, H., Lindros, K., Hekali, P. & Salaspuro, M. Elevated blood acetate as indicator of fast ethanol elimination in chronic alcoholics. Alcohol 2, 623–626 (1985).

    Article  CAS  PubMed  Google Scholar 

  21. Lundquist, F., Tygstrup, N., Winkler, K., Mellemgaard, K. & Munck-Petersen, S. Ethanol metabolism and production of free acetate in the human liver. J. Clin. Invest. 41, 955–961 (1962).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Seitz, H. K. & Stickel, F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat. Rev. Cancer 7, 599–612 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Kendrick, S. F. et al. Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis. Hepatology 51, 1988–1997 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Schug, Z. T. et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27, 57–71 (2015). This study identified ACSS2 as a key enzyme for cancer cell growth under 'tumour-like' conditions of low lipid availability and hypoxia. It also showed that ACSS2 was highly upregulated under these same conditions and that depletion of ACSS2 inhibited tumour growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591–1602 (2014). This was the first paper to study Acss2−/− mice in two different mouse models of liver cancer and showed that loss of ACSS2 decreased tumour burden.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fleming, S. E., Choi, S. Y. & Fitch, M. D. Absorption of short-chain fatty acids from the rat cecum in vivo. J. Nutr. 121, 1787–1797 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Reynolds, D. A., Rajendran, V. M. & Binder, H. J. Bicarbonate-stimulated [14C]butyrate uptake in basolateral membrane vesicles of rat distal colon. Gastroenterology 105, 725–732 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Chu, S. & Montrose, M. H. Extracellular pH regulation in microdomains of colonic crypts: effects of short-chain fatty acids. Proc. Natl Acad. Sci. USA 92, 3303–3307 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Miyauchi, S., Gopal, E., Fei, Y. J. & Ganapathy, V. Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na+-coupled transporter for short-chain fatty acids. J. Biol. Chem. 279, 13293–13296 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Coady, M. J. et al. The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J. Physiol. 557, 719–731 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li, H. et al. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc. Natl Acad. Sci. USA 100, 8412–8417 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lin, H. Y. et al. Protein expressions and genetic variations of SLC5A8 in prostate cancer risk and aggressiveness. Urology 78, 971.e1–971.e9 (2011).

    Article  Google Scholar 

  33. Ullah, M. S., Davies, A. J. & Halestrap, A. P. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1α-dependent mechanism. J. Biol. Chem. 281, 9030–9037 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Parks, S. K., Chiche, J. & Pouyssegur, J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat. Rev. Cancer 13, 611–623 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Kirat, D. & Kato, S. Monocarboxylate transporter 1 (MCT1) mediates transport of short-chain fatty acids in bovine caecum. Exp. Physiol. 91, 835–844 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Pinheiro, C. et al. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch. 452, 139–146 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Moschen, I., Broer, A., Galic, S., Lang, F. & Broer, S. Significance of short chain fatty acid transport by members of the monocarboxylate transporter family (MCT). Neurochem. Res. 37, 2562–2568 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Jackson, V. N. & Halestrap, A. P. The kinetics, substrate, and inhibitor specificity of the monocarboxylate (lactate) transporter of rat liver cells determined using the fluorescent intracellular pH indicator, 2′,7′-bis(carboxyethyl)-5(6)-carboxyfluorescein. J. Biol. Chem. 271, 861–868 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Olivares, O., Dabritz, J. H., King, A., Gottlieb, E. & Halsey, C. Research into cancer metabolomics: towards a clinical metamorphosis. Semin. Cell Dev. Biol. 43, 52–64 (2015).

    Article  PubMed  Google Scholar 

  40. Bola, B. M. et al. Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport. Mol. Cancer Ther. 13, 2805–2816 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fujino, T., Kondo, J., Ishikawa, M., Morikawa, K. & Yamamoto, T. T. Acetyl-CoA synthetase 2, a mitochondrial matrix enzyme involved in the oxidation of acetate. J. Biol. Chem. 276, 11420–11426 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Luong, A., Hannah, V. C., Brown, M. S. & Goldstein, J. L. Molecular characterization of human acetyl-CoA synthetase, an enzyme regulated by sterol regulatory element-binding proteins. J. Biol. Chem. 275, 26458–26466 (2000). This is a seminal paper describing the molecular characterization of transcriptional regulation of ACSS2.

    Article  CAS  PubMed  Google Scholar 

  43. Watkins, P. A., Maiguel, D., Jia, Z. & Pevsner, J. Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J. Lipid Res. 48, 2736–2750 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Tucek, S. Subcellular distribution of acetyl-CoA synthetase, ATP citrate lyase, citrate synthase, choline acetyltransferase, fumarate hydratase and lactate dehydrogenase in mammalian brain tissue. J. Neurochem. 14, 531–545 (1967).

    Article  CAS  PubMed  Google Scholar 

  45. Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Zaidi, N., Royaux, I., Swinnen, J. V. & Smans, K. ATP citrate lyase knockdown induces growth arrest and apoptosis through different cell- and environment-dependent mechanisms. Mol. Cancer Ther. 11, 1925–1935 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bauer, D. E., Hatzivassiliou, G., Zhao, F., Andreadis, C. & Thompson, C. B. ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24, 6314–6322 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Spriet, L. L. et al. Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting. J. Appl. Physiol. 96, 2082–2087 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Kamphorst, J. J., Chung, M. K., Fan, J. & Rabinowitz, J. D. Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate. Cancer Metab. 2, 23 (2014). This paper provides the first description of the lipogenic substrate gap that occurs particularly under hypoxic conditions. It identified acetate as the additional source of lipogenic acetyl-CoA.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603–1614 (2014). This is a landmark paper describing the tissue-specific enhancement of acetate oxidation by glioblastomas and brain metastases (regardless of their tissue of origin).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kuhajda, F. P. et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc. Natl Acad. Sci. USA 91, 6379–6383 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xu, M. et al. An acetate switch regulates stress erythropoiesis. Nat. Med. 20, 1018–1026 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Maher, E. A. et al. Metabolism of [U-13C]glucose in human brain tumors in vivo. NMR Biomed. 25, 1234–1244 (2012). This was the original paper describing how the infusion of patients with stable isotope tracers revealed the bioenergetic substrate gap in brain tumours.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bjornson, E. et al. Stratification of hepatocellular carcinoma patients based on acetate utilization. Cell Rep. 13, 2014–2026 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Schug, Z. T., Vande Voorde, J. & Gottlieb, E. The nurture of tumors can drive their metabolic phenotype. Cell Metab. 23, 391–392 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Davidson, S. M. et al. Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab. 23, 517–528 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. McBrian, M. A. et al. Histone acetylation regulates intracellular pH. Mol. Cell 49, 310–321 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Takahashi, H., McCaffery, J. M., Irizarry, R. A. & Boeke, J. D. Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. Mol. Cell 23, 207–217 (2006). The role of acetyl-CoA synthetases in the regulation of histone acetylation was first identified in yeast.

    Article  CAS  PubMed  Google Scholar 

  61. Gao, X. et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat. Commun. 7, 11960 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen, R. et al. The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment. PLoS ONE 10, e0116515 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fan, J., Krautkramer, K. A., Feldman, J. L. & Denu, J. M. Metabolic regulation of histone post-translational modifications. ACS Chem. Biol. 10, 95–108 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rajendran, P., Williams, D. E., Ho, E. & Dashwood, R. H. Metabolism as a key to histone deacetylase inhibition. Crit. Rev. Biochem. Mol. Biol. 46, 181–199 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Martinez-Pastor, B., Cosentino, C. & Mostoslavsky, R. A tale of metabolites: the cross-talk between chromatin and energy metabolism. Cancer Discov. 3, 497–501 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yoshii, Y. et al. Cytosolic acetyl-CoA synthetase affected tumor cell survival under hypoxia: the possible function in tumor acetyl-CoA/acetate metabolism. Cancer Sci. 100, 821–827 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Sonveaux, P. et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 118, 3930–3942 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chen, R., Dioum, E. M., Hogg, R. T., Gerard, R. D. & Garcia, J. A. Hypoxia increases sirtuin 1 expression in a hypoxia-inducible factor-dependent manner. J. Biol. Chem. 286, 13869–13878 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Starai, V. J., Celic, I., Cole, R. N., Boeke, J. D. & Escalante-Semerena, J. C. Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine. Science 298, 2390–2392 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Schwer, B., Bunkenborg, J., Verdin, R. O., Andersen, J. S. & Verdin, E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl Acad. Sci. USA 103, 10224–10229 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hallows, W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl Acad. Sci. USA 103, 10230–10235 (2006). References 72 and 73 were the first reports of the regulation of ACSS1 and ACSS2 by reversible acetylation, in part controlled by SIRTs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Brown, A. J. et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312–11319 (2003). This is a seminal paper that initially identified and characterized the acetate receptors.

    Article  CAS  PubMed  Google Scholar 

  75. Priyadarshini, M. et al. An acetate-specific GPCR, FFAR2, regulates insulin secretion. Mol. Endocrinol. 29, 1055–1066 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tang, C. et al. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat. Med. 21, 173–177 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. Ge, H. et al. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology 149, 4519–4526 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Hong, Y. H. et al. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 146, 5092–5099 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Peck, B. et al. Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments. Cancer Metab. 4, 6 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Correa-Oliveira, R., Fachi, J. L., Vieira, A., Sato, F. T. & Vinolo, M. A. Regulation of immune cell function by short-chain fatty acids. Clin. Transl Immunol. 5, e73 (2016).

    Article  CAS  Google Scholar 

  83. Hatanaka, H. et al. Identification of transforming activity of free fatty acid receptor 2 by retroviral expression screening. Cancer Sci. 101, 54–59 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Tang, Y., Chen, Y., Jiang, H., Robbins, G. T. & Nie, D. G-Protein-coupled receptor for short-chain fatty acids suppresses colon cancer. Int. J. Cancer 128, 847–856 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Yonezawa, T., Kobayashi, Y. & Obara, Y. Short-chain fatty acids induce acute phosphorylation of the p38 mitogen-activated protein kinase/heat shock protein 27 pathway via GPR43 in the MCF-7 human breast cancer cell line. Cell. Signal. 19, 185–193 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Shou, Y., Lu, J., Chen, T., Ma, D. & Tong, L. Correlation of fluorodeoxyglucose uptake and tumor-proliferating antigen Ki-67 in lymphomas. J. Cancer Res. Ther. 8, 96–102 (2012).

    Article  PubMed  Google Scholar 

  87. Riedl, C. C. et al. 18F-FDG PET scanning correlates with tissue markers of poor prognosis and predicts mortality for patients after liver resection for colorectal metastases. J. Nucl. Med. 48, 771–775 (2007).

    Article  PubMed  Google Scholar 

  88. Gillies, R. J., Schornack, P. A., Secomb, T. W. & Raghunand, N. Causes and effects of heterogeneous perfusion in tumors. Neoplasia 1, 197–207 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yamamoto, Y. et al. 11C-acetate PET in the evaluation of brain glioma: comparison with 11C-methionine and 18F-FDG-PET. Mol. Imaging Biol. 10, 281–287 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Wong, T. Z., van der Westhuizen, G. J. & Coleman, R. E. Positron emission tomography imaging of brain tumors. Neuroimaging Clin. N. Am. 12, 615–626 (2002).

    Article  PubMed  Google Scholar 

  91. Yoshii, Y., Furukawa, T., Saga, T. & Fujibayashi, Y. Acetate/acetyl-CoA metabolism associated with cancer fatty acid synthesis: overview and application. Cancer Lett. 356, 211–216 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Vavere, A. L., Kridel, S. J., Wheeler, F. B. & Lewis, J. S. 1-11C-acetate as a PET radiopharmaceutical for imaging fatty acid synthase expression in prostate cancer. J. Nucl. Med. 49, 327–334 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Oyama, N. et al. 11C-acetate PET imaging of prostate cancer. J. Nucl. Med. 43, 181–186 (2002).

    CAS  PubMed  Google Scholar 

  94. Ponde, D. E. et al. 18F-fluoroacetate: a potential acetate analog for prostate tumor imaging—in vivo evaluation of 18F-fluoroacetate versus 11C-acetate. J. Nucl. Med. 48, 420–428 (2007).

    CAS  PubMed  Google Scholar 

  95. Jadvar, H. Prostate cancer: PET with 18F-FDG, 18F- or 11C-acetate, and 18F- or 11C-choline. J. Nucl. Med. 52, 81–89 (2011).

    Article  PubMed  Google Scholar 

  96. Brogsitter, C., Zophel, K. & Kotzerke, J. 18F-Choline, 11C-choline and 11C-acetate PET/CT: comparative analysis for imaging prostate cancer patients. Eur. J. Nucl. Med. Mol. Imaging 40 (Suppl. 1), S18–S27 (2013).

    Google Scholar 

  97. Schiepers, C. et al. 1-11C-acetate kinetics of prostate cancer. J. Nucl. Med. 49, 206–215 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Mena, E. et al. 11C-Acetate PET/CT in localized prostate cancer: a study with MRI and histopathologic correlation. J. Nucl. Med. 53, 538–545 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Oyama, N. et al. 11C-Acetate PET imaging for renal cell carcinoma. Eur. J. Nucl. Med. Mol. Imaging 36, 422–427 (2009).

    Article  PubMed  Google Scholar 

  100. Park, J. W. et al. A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma. J. Nucl. Med. 49, 1912–1921 (2008).

    Article  PubMed  Google Scholar 

  101. Lewis, D. Y. et al. Late imaging with [1-11C]acetate improves detection of tumor fatty acid synthesis with PET. J. Nucl. Med. 55, 1144–1149 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Tsuchida, T., Takeuchi, H., Okazawa, H., Tsujikawa, T. & Fujibayashi, Y. Grading of brain glioma with 1-11C-acetate PET: comparison with 18F-FDG PET. Nucl. Med. Biol. 35, 171–176 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Ho, C. L. et al. 11C-acetate PET/CT for metabolic characterization of multiple myeloma: a comparative study with 18F-FDG PET/CT. J. Nucl. Med. 55, 749–752 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Seltzer, M. A. et al. Radiation dose estimates in humans for 11C-acetate whole-body PET. J. Nucl. Med. 45, 1233–1236 (2004).

    CAS  PubMed  Google Scholar 

  105. Hensley, C. T. et al. Metabolic heterogeneity in human lung tumors. Cell 164, 681–694 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Peters, S. G., Pomare, E. W. & Fisher, C. A. Portal and peripheral blood short chain fatty acid concentrations after caecal lactulose instillation at surgery. Gut 33, 1249–1252 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dankert, J., Zijlstra, J. B. & Wolthers, B. G. Volatile fatty acids in human peripheral and portal blood: quantitative determination vacuum distillation and gas chromatography. Clin. Chim. Acta 110, 301–307 (1981).

    Article  CAS  PubMed  Google Scholar 

  108. Gregory, J. F. 3rd et al. Metabolomic analysis reveals extended metabolic consequences of marginal vitamin B-6 deficiency in healthy human subjects. PLoS ONE 8, e63544 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Pouteau, E. et al. Production rate of acetate during colonic fermentation of lactulose: a stable-isotope study in humans. Am. J. Clin. Nutr. 68, 1276–1283 (1998).

    Article  CAS  PubMed  Google Scholar 

  110. Pouteau, E., Meirim, I., Metairon, S. & Fay, L. B. Acetate, propionate and butyrate in plasma: determination of the concentration and isotopic enrichment by gas chromatography/mass spectrometry with positive chemical ionization. J. Mass Spectrom. 36, 798–805 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Robertson, M. D., Bickerton, A. S., Dennis, A. L., Vidal, H. & Frayn, K. N. Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism. Am. J. Clin. Nutr. 82, 559–567 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Pomare, E. W., Branch, W. J. & Cummings, J. H. Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood. J. Clin. Invest. 75, 1448–1454 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Akanji, A. O., Humphreys, S., Thursfield, V. & Hockaday, T. D. The relationship of plasma acetate with glucose and other blood intermediary metabolites in non-diabetic and diabetic subjects. Clin. Chim. Acta 185, 25–34 (1989).

    Article  CAS  PubMed  Google Scholar 

  114. Akanji, A. O., Ng, L. & Humphreys, S. Plasma acetate levels in response to intravenous fat or glucose/insulin infusions in diabetic and non-diabetic subjects. Clin. Chim. Acta 178, 85–94 (1988).

    Article  CAS  PubMed  Google Scholar 

  115. Crouse, J. R., Gerson, C. D., DeCarli, L. M. & Lieber, C. S. Role of acetate in the reduction of plasma free fatty acids produced by ethanol in man. J. Lipid Res. 9, 509–512 (1968).

    CAS  PubMed  Google Scholar 

  116. Fernandes, J., Vogt, J. & Wolever, T. M. Inulin increases short-term markers for colonic fermentation similarly in healthy and hyperinsulinaemic humans. Eur. J. Clin. Nutr. 65, 1279–1286 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Simoneau, C. et al. Measurement of whole body acetate turnover in healthy subjects with stable isotopes. Biol. Mass Spectrom. 23, 430–433 (1994).

    Article  CAS  PubMed  Google Scholar 

  118. Tollinger, C. D., Vreman, H. J. & Weiner, M. W. Measurement of acetate in human blood by gas chromatography: effects of sample preparation, feeding, and various diseases. Clin. Chem. 25, 1787–1790 (1979).

    CAS  PubMed  Google Scholar 

  119. Pownall, H. J. et al. Effect of moderate alcohol consumption on hypertriglyceridemia: a study in the fasting state. Arch. Intern. Med. 159, 981–987 (1999).

    Article  CAS  PubMed  Google Scholar 

  120. Muir, J. G. et al. Resistant starch in the diet increases breath hydrogen and serum acetate in human subjects. Am. J. Clin. Nutr. 61, 792–799 (1995).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Zachary T. Schug

    Present address: Present address: Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.,

Authors and Affiliations

  1. Cancer Metabolism Research Unit, Cancer Research UK Beatson Institute, Switchback Road, Glasgow, G61 1BD, Scotland, UK

    Zachary T. Schug, Johan Vande Voorde & Eyal Gottlieb

Authors
  1. Zachary T. Schug
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johan Vande Voorde
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eyal Gottlieb
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eyal Gottlieb.

Ethics declarations

Competing interests

MetaboMed Ltd, Israel, Shareholder and Director (E.G.). Z.T.S. and J.V.V. declare no competing interests.

PowerPoint slides

Glossary

Crabtree effect

The phenomenon whereby aerobic fermentation of glucose occurs and respiration is inhibited if the glucose concentration surpasses a threshold value.

Short-chain fatty acids

(SCFAs). Fatty acids with an aliphatic tail of two to six carbon atoms. The SCFAs acetate, propionate and butyrate are abundantly produced by bacterial fermentation of dietary carbohydrates in the colon.

Facultative autotrophs

Organisms that can grow using organic carbon but are also able to assimilate organic carbon from inorganic carbon sources such as CO2.

Lipogenic substrate gap

Alternative carbon sources that contribute to de novo fatty acid synthesis, as a large proportion (20–40%) of carbons in fatty acids in hypoxic cancer cells cannot be attributed to glucose or glutamine.

Bioenergetic substrate gap

Alternative sources of carbon that contribute to tumour bioenergetics, as less than 50% of acetyl-CoA in human brain tumours is derived from blood-borne glucose.

Crotonylation

A post-translational modification of histone lysine residues that has been shown to stimulate transcription and is, at least partially, dependent on acetyl-CoA synthetase 2 (ACSS2)-catalysed production of crotonyl-CoA from the short-chain fatty acid crotonate.

Caloric restriction

Caloric restriction without malnutrition is a dietary strategy that has been studied extensively as a way to slow ageing and extend lifespan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schug, Z., Vande Voorde, J. & Gottlieb, E. The metabolic fate of acetate in cancer. Nat Rev Cancer 16, 708–717 (2016). https://doi.org/10.1038/nrc.2016.87

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc.2016.87

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer