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.
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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.
The authors declare no competing financial interests.
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.
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