Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/199421
Type: Artigo
Title: Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis
Author: Zecchin, Karina G.
Rossato, Franco A.
Raposo, Helena F.
Melo, Daniela R.
Alberici, Luciane C.
Oliveira, Helena C. F.
Castilho, Roger F.
Coletta, Ricardo D.
Vercesi, Aníbal E.
Graner, Edgard
Abstract: 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.
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 crelease 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
Subject: Apoptose
Ácido graxo sintases
Country: Reino Unido
Editor: Springer Nature
Citation: Laboratory Investigation; A Journal Of Technical Methods And Pathology. v. 91, n. 2, p. 232-40, 2011-Feb.
Rights: fechado
Identifier DOI: 10.1038/labinvest.2010.157
Address: https://www.nature.com/articles/labinvest2010157
Date Issue: 2011
Appears in Collections:IB - Artigos e Outros Documentos
FCM - Artigos e Outros Documentos
FOP - Artigos e Outros Documentos

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