[HTML][HTML] Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in …

LS Pike, AL Smift, NJ Croteau, DA Ferrick… - Biochimica et Biophysica …, 2011 - Elsevier
LS Pike, AL Smift, NJ Croteau, DA Ferrick, M Wu
Biochimica et Biophysica Acta (BBA)-Bioenergetics, 2011Elsevier
Normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to
produce adenosine triphosphate to maintain their viability and functions by using three
major bioenergetic fuels: glucose, glutamine and fatty acids. Many cancer cells, however,
rely on aerobic glycolysis for their growth and survival, and recent studies indicate that some
cancer cells depend on glutamine as well. This altered metabolism in cancers occurs
through oncogene activation or loss of tumor suppressor genes in multiple signaling …
Normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to produce adenosine triphosphate to maintain their viability and functions by using three major bioenergetic fuels: glucose, glutamine and fatty acids. Many cancer cells, however, rely on aerobic glycolysis for their growth and survival, and recent studies indicate that some cancer cells depend on glutamine as well. This altered metabolism in cancers occurs through oncogene activation or loss of tumor suppressor genes in multiple signaling pathways, including the phosphoinositide 3-kinase and Myc pathways. Relatively little is known, however, about the role of fatty acids as a bioenergetic fuel in growth and survival of cancer cells. Here, we report that human glioblastoma SF188 cells oxidize fatty acids and that inhibition of fatty acid β-oxidation by etomoxir, a carnitine palmitoyltransferase 1 inhibitor, markedly reduces cellular adenosine triphosphate levels and viability. We also found that inhibition of fatty acid oxidation decreases nicotinamide adenine dinucleotide phosphate levels and the reduced glutathione (GSH) content and elevates intracellular reactive oxygen species. These results suggest that modulation of fatty acid oxidation controls the nicotinamide adenine dinucleotide phosphate level. In the presence of reactive oxygen species scavenger tiron, however, adenosine triphosphate depletion is prevented without restoring fatty acid oxidation. This suggests that oxidative stress may lead to bioenergetic failure and cell death. Our work provides evidence that mitochondrial fatty acid oxidation may provide nicotinamide adenine dinucleotide phosphate for defense against oxidative stress and prevent adenosine triphosphate loss and cell death.
Elsevier