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 c ancer cells in vitro and in vivo without toxicity to proliferating normal c ells, We have previously shown that FAS inhibition causes a rapid increase in malonyl-CoA levels identifying malonyl-CoA as a potential trigger of apo ptosis. In this study we further investigated the role of malonyl-CoA durin g FAS inhibition. We have found that: [i] inhibition of FAS with cerulenin causes carnitine palmitoyltransferase-1 (CPT-1) inhibition and fatty acid o xidation inhibition in MCF-7 human breast cancer cells likely mediated by e levation of malonyl-CoA; [ii] cerulenin cytotoxicity is due to the nonphysi ological state of increased malonyl-CoA, decreased fatty acid oxidation, an d decreased fatty acid synthesis; and [iii] the cytotoxic effect of cerulen in 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. (C) 2001 Academic Press.