ATP Production Relies on Fatty Acid Oxidation Rather than Glycolysis in Pancreatic Ductal Adenocarcinoma

Simple Summary We found a conserved pathway for the energy supply in cancer. The present study revealed that glucose is not a major source of ATP production, whereas fatty acid is a major source of electrons for ATP production through fatty acid oxidation (FAO) and oxidative phosphorylation (OxPhos) in cancer cells. NADH is mainly recruited from FAO, which is used for ATP synthesis via OxPhos with electron transfer complexes in cancer cells while ATP is synthesized from NADH produced in the TCA cycle in the normal cells. Therefore, a calorie-balanced low-fat diet showed 3-fold reduction of tumor formation, whereas a high-fat diet caused a 2-fold increase of tumor to compare to the control in a human pancreatic ductal adenocarcinoma xenograft and a homograft KC models. Glycolysis is known as the main pathway for ATP production in cancer cells. However, in cancer cells, glucose deprivation for 24 h does not reduce ATP levels, whereas it does suppress lactate production. In this study, metabolic pathways were blocked to identify the main pathway of ATP production in pancreatic ductal adenocarcinoma (PDAC). Blocking fatty acid oxidation (FAO) decreased ATP production by 40% in cancer cells with no effect on normal cells. The effects of calorie balanced high- or low-fat diets were tested to determine whether cancer growth is modulated by fatty acids instead of calories. A low-fat diet caused a 70% decrease in pancreatic preneoplastic lesions compared with the control, whereas a high-fat diet caused a two-fold increase in preneoplastic lesions accompanied with increase of ATP production in the Kras (G12D)/Pdx1-cre PDAC model. The present results suggest that ATP production in cancer cells is dependent on FAO rather than on glycolysis, which can be a therapeutic approach by targeting cancer energy metabolism.