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.

  • Progress
  • Published:

Cancer metabolism: fatty acid oxidation in the limelight

Abstract

Warburg suggested that the alterations in metabolism that he observed in cancer cells were due to the malfunction of mitochondria. In the past decade, we have revisited this idea and reached a better understanding of the 'metabolic switch' in cancer cells, including the intimate and causal relationship between cancer genes and metabolic alterations, and their potential to be targeted for cancer treatment. However, the vast majority of the research into cancer metabolism has been limited to a handful of metabolic pathways, while other pathways have remained in the dark. This Progress article brings to light the important contribution of fatty acid oxidation to cancer cell function.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Representation of the β-oxidation of palmitic acid in the mitochondria.
Figure 2: Effect of FAO on cancer cell metabolism, growth and survival.
Figure 3: Summary of the regulation of FAO and its effect on cell fate in cancer cells from different origins.

Similar content being viewed by others

References

  1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  Google Scholar 

  2. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  CAS  Google Scholar 

  3. Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg's contributions to current concepts of cancer metabolism. Nature Rev. Cancer 11, 325–337 (2011).

    Article  CAS  Google Scholar 

  4. Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

    Article  CAS  Google Scholar 

  5. Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genet. 43, 869–874 (2011).

    Article  CAS  Google Scholar 

  6. Vander Heiden, M. G. et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329, 1492–1499 (2010).

    Article  CAS  Google Scholar 

  7. Hitosugi, T. et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell 22, 585–600 (2012).

    Article  CAS  Google Scholar 

  8. DeBerardinis, R. J. et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007).

    Article  CAS  Google Scholar 

  9. Wise, D. R. & Thompson, C. B. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci. 35, 427–433 (2010).

    Article  CAS  Google Scholar 

  10. Singh, R. & Cuervo, A. M. Lipophagy: connecting autophagy and lipid metabolism. Int. J. Cell Biol. 2012, 282041 (2012).

    Article  Google Scholar 

  11. Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009). This study demonstrated for the first time that FAO has a crucial role in the survival of cancer cells under metabolic stress.

    Article  CAS  Google Scholar 

  12. Carracedo, A. et al. A metabolic prosurvival role for PML in breast cancer. J. Clin. Invest. 122, 3088–3100 (2012). This study uncovered a pro-survival activity of the PML tumour suppressor in breast cancer through the regulation of FAO.

    Article  CAS  Google Scholar 

  13. Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011). This study shows that CPT1C overexpression in cancer is important for cancer cell survival and resistance to therapy.

    Article  CAS  Google Scholar 

  14. Carrasco, P. et al. Ceramide levels regulated by carnitine palmitoyltransferase 1C control dendritic spine maturation and cognition. J. Biol. Chem. 287, 21224–21232 (2012).

    Article  CAS  Google Scholar 

  15. Lee, J. & Wolfgang, M. J. Metabolomic profiling reveals a role for CPT1c in neuronal oxidative metabolism. BMC Biochem. 13, 23 (2012).

    Article  CAS  Google Scholar 

  16. Sierra, A. Y. et al. CPT1c is localized in endoplasmic reticulum of neurons and has carnitine palmitoyltransferase activity. J. Biol. Chem. 283, 6878–6885 (2008).

    Article  CAS  Google Scholar 

  17. Samudio, I. et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J. Clin. Invest. 120, 142–156 (2010). This study demonstrated the therapeutic potential of FAO inhibition in leukaemia.

    Article  CAS  Google Scholar 

  18. Giordano, A. et al. tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1. Cell Death Differ. 12, 603–613 (2005).

    Article  CAS  Google Scholar 

  19. Paumen, M. B. et al. Direct interaction of the mitochondrial membrane protein carnitine palmitoyltransferase I with Bcl-2. Biochem. Biophys. Res. Commun. 231, 523–525 (1997).

    Article  CAS  Google Scholar 

  20. Vickers, A. E. Characterization of hepatic mitochondrial injury induced by fatty acid oxidation inhibitors. Toxicol. Pathol. 37, 78–88 (2009).

    Article  CAS  Google Scholar 

  21. Samudio, I., Fiegl, M., McQueen, T., Clise-Dwyer, K. & Andreeff, M. The warburg effect in leukemia-stroma cocultures is mediated by mitochondrial uncoupling associated with uncoupling protein 2 activation. Cancer Res. 68, 5198–5205 (2008).

    Article  CAS  Google Scholar 

  22. Monti, S. et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 105, 1851–1861 (2005).

    Article  CAS  Google Scholar 

  23. Caro, P. et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 22, 547–560 (2012).

    Article  CAS  Google Scholar 

  24. Ito, K. et al. A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nature Med. 18, 1350–1358 (2012).

    Article  CAS  Google Scholar 

  25. Gan, B. et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature 468, 701–704 (2011).

    Article  Google Scholar 

  26. Gurumurthy, S. et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659–663 (2011).

    Article  Google Scholar 

  27. Nakada, D., Saunders, T. L. & Morrison, S. J. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468, 653–658 (2011).

    Article  Google Scholar 

  28. Knobloch, M. et al. Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis. Nature 493, 226–230 (2013).

    Article  CAS  Google Scholar 

  29. Valent, P. et al. Cancer stem cell definitions and terminology: the devil is in the details. Nature Rev. Cancer 12, 767–775 (2012).

    Article  CAS  Google Scholar 

  30. Chiarugi, A., Dolle, C., Felici, R. & Ziegler, M. The NAD metabolome--a key determinant of cancer cell biology. Nature Rev. Cancer 12, 741–752 (2012).

    Article  CAS  Google Scholar 

  31. Pike, L. S., Smift, A. L., Croteau, N. J., Ferrick, D. A. & Wu, M. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim. Biophys. Acta 1807, 726–734 (2011).

    Article  CAS  Google Scholar 

  32. Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012). This study demonstrated that FAO counteracts the accumulation of ROS in conditions of metabolic stress through the generation of NADPH.

    Article  CAS  Google Scholar 

  33. Mihaylova, M. M. & Shaw, R. J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nature Cell Biol. 13, 1016–1023 (2011).

    Article  CAS  Google Scholar 

  34. Diradourian, C., Girard, J. & Pegorier, J. P. Phosphorylation of PPARs: from molecular characterization to physiological relevance. Biochimie 87, 33–38 (2005).

    Article  CAS  Google Scholar 

  35. Hosokawa, K. et al. Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction. Biochem. Biophys. Res. Commun. 363, 578–583 (2007).

    Article  CAS  Google Scholar 

  36. Ito, K. et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nature Med. 12, 446–451 (2006).

    Article  CAS  Google Scholar 

  37. Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).

    Article  CAS  Google Scholar 

  38. Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Med. 17, 1498–1503 (2011).

    Article  CAS  Google Scholar 

  39. Abu-Elheiga, L. et al. The subcellular localization of acetyl-CoA carboxylase 2. Proc. Natl Acad. Sci. USA97, 1444–1449 (2000).

    Article  Google Scholar 

  40. Holubarsch, C. J. et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study. Clin. Sci. (Lond.) 113, 205–212 (2007).

    Article  CAS  Google Scholar 

  41. Kantor, P. F., Lucien, A., Kozak, R. & Lopaschuk, G. D. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ. Res. 86, 580–588 (2000).

    Article  CAS  Google Scholar 

  42. Nash, D. T. & Nash, S. D. Ranolazine for chronic stable angina. Lancet 372, 1335–1341 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors apologize to those whose publications related to the discussed issues could not be cited owing to space limitations. The authors would like to thank the members of the Carracedo laboratory (N. Martín, V. Torrano, A. Zabala, A. Arruabarrena, P. Zuñiga and S. Fernández) for the insightful discussion and critical comments. The work of A.C. is supported by the Ramón y Cajal award (Spanish Ministry of Education), the Basque Department of Industry, Tourism and Trade (Etortek), Marie Curie Reintegration grant (277043), Movember Global Action Plan, ISCIII (PI10/01484) and the Basque Government of health (2012111086) and education (PI2012-03). The work of P.P.P. is supported by grants from the US National Cancer Institute (NCI). The work of L.C.C. is supported by grants from both the US National Institutes of Health and the NCI.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Arkaitz Carracedo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

FURTHER INFORMATION

Arkaitz Carracedo's homepage

Glossary

Anoikis

An apoptotic process activated as a result of insufficient or inadequate cell–matrix interactions. This process can be observed during development and epithelial hyperproliferation or can be induced experimentally.

Fatty acid synthase

(FASN). This protein has eight different enzymatic activities in a single polypeptidic chain and gives rise to palmitic acid (16:0).

Oxidative phosphorylation

(OXPHOS). The oxidation of reduced NAD and FAD for the production of ATP, creating an exchange of electrons between donors and acceptors (oxygen) and a proton gradient between the intermembrane space and the lumen of the mitochondria. This process is carried out by the electron transport chain at the inner mitochondrial membrane and favours the generation of ATP by ATP synthase while dissipating the proton gradient.

Pentose phosphate pathway

(PPP). This metabolic pathway generates pentoses and NADPH, which are both required for cell growth and proliferation. Through its oxidative branch, glucose-6-phosphate is oxidized to generate ribulose-5-phosphate (for nucleotide synthesis) and NADPH for anabolism.

Warburg's hypothesis

Otto Warburg observed that cancer cells, in the presence of oxygen, metabolize glucose anaerobically, leading to the production of lactate, instead of oxidizing it through the Krebs cycle. Thus, he hypothesized that cancer cells had dysfunctional mitochondria, and this metabolic rewiring was termed the Warburg effect.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carracedo, A., Cantley, L. & Pandolfi, P. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 13, 227–232 (2013). https://doi.org/10.1038/nrc3483

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3483

This article is cited by

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