Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity.
Inhibition of fatty acid synthase (FAS) induces apoptosis in human breast cancer cells in vitro and in vivo without toxicity to proliferating normal cells. We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apoptosis. In this study we further investigated the role of malonyl-CoA during FAS inhibition. We have found that: [i] inhibition of FAS with cerulenin causes carnitine palmitoyltransferase-1 (CPT-1) inhibition and fatty acid oxidation inhibition in MCF-7 human breast cancer cells likely mediated by elevation of malonyl-CoA; [ii] cerulenin cytotoxicity is due to the nonphysiological state of increased malonyl-CoA, decreased fatty acid oxidation, and decreased fatty acid synthesis; and [iii] the cytotoxic effect of cerulenin can be mimicked by simultaneous inhibition of CPT-1, with etomoxir, and fatty acid synthesis with TOFA, an acetyl-CoA carboxylase (ACC) inhibitor. This study identifies CPT-1 and ACC as two new potential targets for cancer chemotherapy.
Thupari
J N
JN
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Pinn
M L
ML
Kuhajda
F P
FP
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000187:drug effects; D002569:Cerulenin / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005663:Furans / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007700:Kinetics; D008316:Malonyl Coenzyme A / Q000378:metabolism* / Q000633:toxicity; D008954:Models, Biological; D010084:Oxidation-Reduction; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D005663:Furans; D000960:Hypolipidemic Agents; D002569:Cerulenin; D008316:Malonyl Coenzyme A; C014289:5-(tetradecyloxy)-2-furancarboxylic acid; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase; C054207:etomoxir