Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model

Autor(es):Mostrar menos -

Carvalho, Marco A. ^[1] ; Zecchin, Karina G. ^[2] ; Seguin, Fabiana ^[1] ; Bastos, Debora C. ^[1] ; Agostini, Michelle ^[1] ; Rangel, Ana Lcia C. A. ^[1] ; Veiga, Silvio S. ^[3] ; Raposo, Helena F. ^[4] ; Oliveira, Helena C. F. ^[4] ; Loda, Massimo ^{[5, 6]} ; Coletta, Ricardo D. ^[1] ; Graner, Edgard ^[1]

Afiliação do(s) autor(es)

^[1] State Univ Campinas UNICAMP, Sch Dent Piracicaba, Dept Oral Diag, BR-13414018 Piracicaba, SP - Brazil

^[2] State Univ Campinas UNICAMP, Sch Med Sci, Dept Clin Pathol, Campinas, SP - Brazil

^[3] Univ Fed Parana, Dept Cell Biol, BR-80060000 Curitiba, Parana - Brazil

^[4] State Univ Campinas UNICAMP, Inst Biol, Dept Physiol & Biophys, Campinas, SP - Brazil

^[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 - USA

^[6] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 - USA

• Tipo de documento: Artigo Científico
• Fonte: International Journal of Cancer; v. 123, n. 11, p. 2557-2565, DEC 1 2008.
• Citações Web of Science: 90

Resumo

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 F FASN activity could have a potential benefit in association with the current chemotherapy for melanoma. (C) 2008 Wiley-Liss, Inc. (AU)

• Processo FAPESP: 04/13904-6 - Estudo do papel biológico da interação entre a isopeptidase USP2a e a enzima anabólica ácido graxo sintase em linhagens celulares derivadas de melanoma humano e murino
• Beneficiário: Ana Lúcia Carrinho Ayroza Rangel
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 05/50297-3 - Estudo da expressão da isopeptidase Ubp-69 (USP2a) em linhagens celulares de melanoma
• Beneficiário: Fabiana Seguin
• Linha de fomento: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 04/13903-0 - Estudo da interação entre a isopeptidase USP2a e a enzima anabólica ácido graxo sintase e seus efeitos na regulação de p27k'P' em linhagens celulares derivadas de melanoma humano e murino
• Beneficiário: Edgard Graner
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 04/06397-0 - Estudo da expressão da enzima desubiquitinante USP2a e de seu papel biológico em células derivadas de carcinomas espinocelulares bucais humanos
• Beneficiário: Michelle Agostini
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 05/52631-8 - Análise do papel da enzima ácido graxo sintase no processo metastático de melanoma em modelo murino (B16F10 / C57BL6)
• Beneficiário: Marco Antonio Carvalho
• Linha de fomento: Bolsas no Brasil - Mestrado
• Processo FAPESP: 02/08030-1 - Estudo das enzimas desubiquitinantes Ubp-45(USP9) e Ubp-69 (USP2) no controle da proliferação de linhagens celulares de carcinoma bucal e de fibromatose gengival hereditária
• Beneficiário: Edgard Graner
• Linha de fomento: Auxílio à Pesquisa - Regular