Deciphering Fatty Acid Synthase Inhibition-Triggered Metabolic Flexibility in Prostate Cancer Cells through Untargeted Metabolomics

Abstract

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.

De novo lipogenesis pathway is a vulnerability in IDH1 mutant glioma

“…In breast cancer cells, FASN inhibition has been found to increase unsaturated fatty acids, ceramides, and diacylglycerols 33 . In prostate cancer cells, inhibition of FASN by multiple FASN inhibitors increased synthesis of long chain unsaturated fatty acids and phospholipids 34 . This suggests that cancer cells potentially upregulate multiple other metabolic pathways to compensate for FASN inhibition and this may be conserved among multiple cancer types.…”

Concomitant Inhibition of FASN and SREBP Provides a Promising Therapy for CTCL

“…Interestingly, despite the potent impact of FASN inhibitors on cell viability, we found that Orlistat elicited an increase in FASN expression, which led us to hypothesize that this could be triggered by a feedback mechanism because of high metabolic flexibilities in tumour cells [ 57 ]. Considering that SREBPs are pivotal transcription factors in lipid homeostasis, which oneself can also be regulated by lipid abundance, the SREBP inhibitor Fatostatin was selected to contend against the upregulation of FASN induced by FASN inhibitors.…”

An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis

“…Treatment of the LNCaP-LN3 prostate cancer cell line with the FASN inhibitor TVB-3166 decreased palmitate content, resulting in the accumulation of total lipids, whereas supplementation with palmitate reversed the acquisition of this phenotype 92 . In contrast to that in KRAS -mutant lung cancer cells, the increase in total lipids in prostate cancer cells was not due to an increase in fatty acid uptake because similar lipidomic changes were observed under serum-free conditions 92 . A lipidomic analysis showed that several lipids, such as PE, PC, and LPC, accumulated after FASN inhibition, implying that the Kennedy pathway was activated to compensate for palmitate depletion 92 .…”