title: Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model.
abstract: Fatty acid synthase (FASN) is the enzyme responsible for the endogenous synthesis of the saturated fatty acid palmitate. In contrast to most normal cells, malignant cells depend on FASN activity for growth and survival. In fact, FASN is overexpressed in a variety of human cancers including cutaneous melanoma, in which its levels of expression are associated with a poor prognosis and depth of invasion. Here, we show that the specific inhibition of FASN activity by the antiobesity drug Orlistat or siRNA is able to significantly reduce proliferation and promote apoptosis in the mouse metastatic melanoma cell line B16-F10. These results prompted us to verify the effect of FASN inhibition on the metastatic process in a model of spontaneous melanoma metastasis, in which B16-F10 cells injected in the peritoneal cavity of C57BL/6 mice metastasize to the mediastinal lymph nodes. We observed that mice treated with Orlistat 48 hr after the inoculation of B16-F10 cells exhibited a 52% reduction in the number of mediastinal lymph node metastases, in comparison with the control animals. These results suggest that FASN activity is essential for B16-F10 melanoma cell proliferation and survival while its inactivation by Orlistat significantly reduces their metastatic spread. The chemical inhibition of FASN activity could have a potential benefit in association with the current chemotherapy for melanoma.
authors.affiliation: Department of Oral Diagnosis, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), Piracicaba, Sao Paulo, Brazil.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Carvalho
authors.forename: Karina G
authors.initials: KG
authors.lastname: Zecchin
authors.forename: Fabiana
authors.initials: F
authors.lastname: Seguin
authors.forename: Débora C
authors.initials: DC
authors.lastname: Bastos
authors.forename: Michelle
authors.initials: M
authors.lastname: Agostini
authors.forename: Ana Lúcia C A
authors.initials: AL
authors.lastname: Rangel
authors.forename: Sílvio S
authors.initials: SS
authors.lastname: Veiga
authors.forename: Helena F
authors.initials: HF
authors.lastname: Raposo
authors.forename: Helena C F
authors.initials: HC
authors.lastname: Oliveira
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Ricardo D
authors.initials: RD
authors.lastname: Coletta
authors.forename: Edgard
authors.initials: E
authors.lastname: Graner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology* / Q000627:therapeutic use*; D008207:Lymphatic Metastasis / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D000077403:Orlistat; D010534:Peritoneal Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control
chemical_list: D007783:Lactones; D000077403:Orlistat; D064429:Fatty Acid Synthases