Abstract
Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular effects of triclosan in a panel of eight malignant and non-malignant prostate cell lines to the well-known FASN inhibitors C75 and orlistat, which target different partial catalytic activities of FASN. Triclosan displayed a superior cytotoxic profile with a several-fold lower IC50 than C75 or orlistat. Structure-function analysis revealed that alcohol functionality of the parent phenol is critical for inhibitory action. Rescue experiments confirmed that end product starvation was a major cause of cytotoxicity. Importantly, triclosan, C75 and orlistat induced distinct changes to morphology, cell cycle, lipid content and the expression of key enzymes of lipid metabolism, demonstrating that inhibition of different partial catalytic activities of FASN activates different metabolic pathways. These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer.
Highlights
Fatty acid synthase (FASN) is a key metabolic enzyme that catalyzes in a stepwise and sequential manner the de novo synthesis of fatty acids (FA), predominantly palmitate, from the condensation of seven molecules of malonyl-CoA and one molecule of acetylCoA
Triclosan is cytotoxic in prostate cancer cells
In order to evaluate the effect of the FASN inhibitor triclosan (TCS) on the growth of the prostate cancer (PCa) cell line LNCaP and to compare its activity to other FASN inhibitors, we treated cells with TCS (2.5-20 M), C75 (5-50 μM) or orlistat (10-80 μM) and measured cell confluence by live imaging for 96 hours (Fig. 1A)
Summary
Fatty acid synthase (FASN) is a key metabolic enzyme that catalyzes in a stepwise and sequential manner the de novo synthesis of fatty acids (FA), predominantly palmitate, from the condensation of seven molecules of malonyl-CoA and one molecule of acetylCoA. This NADPH-dependent process plays a central role in energy homeostasis by converting excess carbon intake into FAs for storage [1]. In prostate cancer (PCa), elevated levels of FASN have been linked to poor prognosis, reduced disease-free survival, aggressiveness of disease, and increased risk of death (reviewed in [3]). Knockdown or pharmacological inhibition of FASN selectively induces cell death of cancer cells and a reduction in tumor volume in xenograft mouse models with only a minimal effect on normal cells, indicating that FASN is a promising target for cancer treatment with the potential for a large therapeutic index (reviewed in [4])
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