Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis.
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.
Zecchin
Karina G
KG
Departamento de Diagnóstico Oral, Faculdade de Odontologia de Piracicaba, Universidade Estadual de Campinas, Piracicaba, São Paulo, Brazil.
Rossato
Franco A
FA
Raposo
Helena F
HF
Melo
Daniela R
DR
Alberici
Luciane C
LC
Oliveira
Helena C F
HC
Castilho
Roger F
RF
Coletta
Ricardo D
RD
Vercesi
Aníbal E
AE
Graner
Edgard
E
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002569:Cerulenin / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D054872:Fatty Acid Synthesis Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D007783:Lactones / Q000494:pharmacology*; D008055:Lipids / Q000096:biosynthesis; D008545:Melanoma / Q000201:enzymology* / Q000503:physiopathology; D051379:Mice; D000077403:Orlistat; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism
D017931:DNA Primers; D054872:Fatty Acid Synthesis Inhibitors; D007783:Lactones; D008055:Lipids; D017382:Reactive Oxygen Species; D002569:Cerulenin; D045304:Cytochromes c; D000077403:Orlistat; D064429:Fatty Acid Synthases; D020169:Caspases; D002118:Calcium