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

Ju Eun Oh,Hyunbeom Lee,Jinyoung Park,Byung Hwa Jung,Soosung Kang

doi:10.3390/cells9112447

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.

Highlights

Fatty acid synthase (FAS) is a multi-enzyme complex that synthesizes palmitic acid, a saturated fatty acid, through the condensation reaction of acetyl-CoA and malonyl-CoA, and it is a key enzyme involved in de novo lipogenesis
To characterize the effects of FAS inhibitors on cancer cell growth and survival, studies were performed to assess the effect of FAS inhibition
The prostate cancer cell line was examined after treatment with different concentrations of Fasnall, GSK2194069, and TVB-3166

Summary

Introduction

Fatty acid synthase (FAS) is a multi-enzyme complex that synthesizes palmitic acid, a saturated fatty acid, through the condensation reaction of acetyl-CoA and malonyl-CoA, and it is a key enzyme involved in de novo lipogenesis. FAS is composed of two identical multifunctional monomers, each including seven different catalytic domains [1]. Lipids play a very important role in tumor cells and are involved in membrane biosynthesis, protein modification, and cell proliferation. FAS is overexpressed in advanced cancers, while it is expressed at low levels in normal tissues due to a strict downregulation by the intake of fats and hormones [5]. It has been reported to be highly expressed in various cancers, such as breast cancer, colorectal cancer, stomach

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Conclusion