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.

Figure 1. Representation of the β-oxidation of palmitic acid in the mitochondria

AcylCoAs enter the fatty acid oxidation (FAO) pathway in which they are dehydrogenated, hydrated and decarboxylated cyclically, which results in the progressive shortening of the fatty acid. The production of NADH and FADH₂ will be used for ATP production in the electron transport chain, and acetyl CoA can enter the Krebs cycle. S-CoA, free coenzme A.

Figure 2. Effect of FAO on cancer cell metabolism, growth and survival

A schematic representation of the metabolic routes interconnected with fatty acid oxidation (FAO) is shown. Central metabolic processes are depicted such as glycolysis, the pentose phosphate pathway (PPP), the Krebs cycle, the electron transport chain (ETC) and FAO. Fatty acids for FAO can either be of extracellular origin (through a first shortening in the peroxisomal FAO for very long fatty acids) or be obtained through the metabolism of triglycerides from lipid droplets. The fate of FAO products is summarized. NADH and FADH₂ are oxidized in the ETC for ATP production and acetyl CoA enters the Krebs cycle to produce citrate, which can be exported to the cytoplasm to engage NADPH-producing reactions. Importantly, the accumulation of fatty acids that do not undergo β-oxidation can induce lipotoxicity. Of note, FAO-independent activities of components in this route are depicted. Dashed arrows represent indirect effects or serial reactions. 6PGLDH, 6-phosphogluconate dehydrogenase; α-KG, α-ketoglutarate; ACC, acetyl CoA carboxylase; AMPK, AMP kinase; CPT1, carnitine palmitoyltransferase; FASN, fatty acid synthase; G6PDH, glucose-6-phosphate dehydrogenase; IDH1, isocitrate dehydrogenase 1; ME1, malic enzyme; PC, pyruvate carboxylase; PDK, pyruvate dehydrogenase (PDH) kinase; PEP, phosphoenol pyruvate; PPAR, peroxisome proliferator-activated receptor; UCP, uncoupling protein.

Figure 3. Summary of the regulation of FAO and its effect on cell fate in cancer cells from different origins

Activation of fatty acid oxidation (FAO) by upstream (AMP kinase (AMPK) and promyelocytic leukaemia (PML)–peroxisome proliferator-activated receptor (PPAR) pathways) regulators is shown, and the FAO products relevant for cancer cell function are indicated, together with the biological outcomes derived from FAO activation. Dashed arrows represent indirect effects or serial reactions. ACC, acetyl CoA carboxylase; CPT1, carnitine palmitoyltrans-ferase; DLBCL, diffuse large B cell lymphoma; FASN, fatty acid synthase; G6PDH, glucose-6-phosphate dehydrogenase; HSC, haematopoietic stem cell; LIC, leukaemia-initiating cell; OXPHOS, oxidative phosphorylation; PGC1A, PPARγ coactivator 1α; ROS, reactive oxygen species; UCP, uncoupling protein.