Fatty acid synthase (FAS) is a key
enzyme involved in de novo lipogenesis that produces
lipids that are necessary for cell growth and signal transduction, and it is known to be overexpressed, especially in
cancer cells. Although lipid metabolism alteration is an important metabolic phenotype in
cancer cells, the development of drugs targeting FAS to block
lipid synthesis is hampered by the characteristics of
cancer cells with metabolic flexibility leading to rapid adaptation and resistance. Therefore, to confirm the metabolic alterations at the cellular level during FAS inhibition, we treated LNCaP-LN3
prostate cancer cells with FAS inhibitors (Fasnall,
GSK2194069, and
TVB-3166). With untargeted metabolomics, we observed significant changes in a total of 56 metabolites in the
drug-treated groups. Among the altered metabolites, 28 metabolites were significantly changed in all of the
drug-treated groups. To our surprise, despite the inhibition of FAS, which is involved in
palmitate production, the cells increase their
fatty acids and
glycerophospholipids contents endogenously. Also, some of the notable changes in the metabolic pathways include
polyamine metabolism and energy metabolism. This is the first study to compare and elucidate the effect of FAS inhibition on cellular metabolic flexibility using three different FAS inhibitors through metabolomics. We believe that our results may provide key data for the development of future FAS-targeting drugs.