Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

• Published in: Laboratory investigation Vol. 91; no. 2; pp. 232 - 240
• Main Authors: Zecchin, Karina G, Rossato, Franco A, Raposo, Helena F, Melo, Daniela R, Alberici, Luciane C, Oliveira, Helena CF, Castilho, Roger F, Coletta, Ricardo D, Vercesi, Aníbal E, Graner, Edgard
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.02.2011; Nature Publishing Group US; Nature Publishing Group
• Subjects: 631/45/607/1167; 631/80/642/333; 631/80/82/23; 692/699/67/1813/1634; Analysis of Variance; Animals; apoptosis; Apoptosis - drug effects; Apoptosis - physiology; B16-F10 cells; Biological and medical sciences; Biotechnology; Calcium - metabolism; Caspases - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; cerulenin; Cerulenin - pharmacology; Cytochromes c - metabolism; Dermatology; DNA Primers - genetics; Enzyme-Linked Immunosorbent Assay; fatty acid synthase; Fatty Acid Synthases - antagonists & inhibitors; Fatty Acid Synthesis Inhibitors - pharmacology; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Lactones - pharmacology; Lipids - biosynthesis; Medical sciences; Medicine; Medicine & Public Health; melanoma; Melanoma - enzymology; Melanoma - physiopathology; Mice; Orlistat; Pathology; Reactive Oxygen Species - metabolism; research-article; RNA Interference; Tumors of the skin and soft tissue. Premalignant lesions; apoptosis; cerulenin; melanoma; orlistat; fatty acid synthase; B16-F10 cells; Acyltransferases; Biotechnology; Enzyme; Transferases; Enzyme inhibitor; Triacylglycerol lipase; Esterases; Malignant tumor; Fatty-acid synthase; Carboxylic ester hydrolases; Anti-obesity agent; Cell death; Clinical biology; Malignant melanoma; Orlistat; Hydrolases; Inhibition; Cell; Cancer; Apoptosis
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2010.157

Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long-chain fatty acid, palmitate. In contrast to most normal cells, FASN is overexpressed in a variety of human cancers, including cutaneous melanoma, in which its levels of expression are associated with tumor invasion and poor prognosis. We have previously shown that FASN inhibition with orlistat significantly reduces the number of spontaneous mediastinal lymph node metastases following the implantation of B16-F10 mouse melanoma cells in the peritoneal cavity of C57BL/6 mice. In this study, we investigate the biological mechanisms responsible for the FASN inhibition-induced apoptosis in B16-F10 cells. Both FASN inhibitors, cerulenin and orlistat, significantly reduced melanoma cell proliferation and activated the intrinsic pathway of apoptosis, as demonstrated by the cytochrome c release and caspase-9 and -3 activation. Further, apoptosis was preceded by an increase in both reactive oxygen species production and cytosolic calcium concentrations and independent of p53 activation and mitochondrial permeability transition. Taken together, these findings demonstrate the mitochondrial involvement in FASN inhibition-induced apoptosis in melanoma cells.