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

Author(s)

Zecchin, Karina G. ^{[1, 2]} ; Rossato, Franco A. ^[2] ; Raposo, Helena F. ^[3] ; Melo, Daniela R. ^[2] ; Alberici, Luciane C. ^[4] ; Oliveira, Helena C. F. ^[3] ; Castilho, Roger F. ^[2] ; Coletta, Ricardo D. ^[1] ; Vercesi, Anibal E. ^[2] ; Graner, Edgard ^[1]

Affiliation

^[1] Univ Estadual Campinas UNICAMP, Fac Odontol Piracicaba, Dept Oral Diag, BR-13414018 Sao Paulo - Brazil

^[2] Univ Estadual Campinas UNICAMP, Fac Ciencias Med, Dept Patol Clin, BR-13414018 Sao Paulo - Brazil

^[3] Univ Estadual Campinas UNICAMP, Inst Biol, Dept Fisiol & Biofis, BR-13414018 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Quim & Fis, Sao Paulo - Brazil

• Document type: Journal article
• Source: LABORATORY INVESTIGATION; v. 91, n. 2, p. 232-240, 2010.
• Web of Science Citations: 41

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. Laboratory Investigation (2011) 91, 232-240; doi:10.1038/labinvest.2010.157; published online 30 August 2010 (AU)

• FAPESP's process: 08/57471-7 - The role of fatty acid synthase activity in apoptosis, metastasis and vasculogenesis in melanoma
• Grantee: Edgard Graner
• Support Opportunities: Research Projects - Thematic Grants