The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas

Autor(es):Mostrar menos -

Agostini, Michelle ^{[1, 2]} ; Almeida, Luciana Y. ^[1] ; Bastos, Debora C. ^[1] ; Ortega, Rose M. ^[1] ; Moreira, Fernanda S. ^[1] ; Seguin, Fabiana ^[1] ; Zecchin, Karina G. ^[1] ; Raposo, Helena F. ^[3] ; Oliveira, Helena C. F. ^[3] ; Amoedo, Nivea D. ^[4] ; Salo, Tuula ^{[5, 6, 7]} ; 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 Sao Paulo - Brazil

^[2] Univ Fed Rio de Janeiro, Sch Dent, Dept Oral Diag & Pathol, Rio De Janeiro - Brazil

^[3] State Univ Campinas UNICAMP, Inst Biol, Dept Physiol & Biophys, BR-13414018 Sao Paulo - Brazil

^[4] Univ Fed Rio de Janeiro, Inst Med Biochem, Rio De Janeiro - Brazil

^[5] Oulu Univ Hosp, Oulu - Finland

^[6] Univ Helsinki, Inst Dent, Helsinki - Finland

^[7] Univ Oulu, Inst Dent, Dept Diagnost & Oral Med, Oulu - Finland

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR CANCER THERAPEUTICS; v. 13, n. 3, p. 585-595, MAR 2014.
• Citações Web of Science: 44

Resumo

Fatty acid synthase (FASN) is the biosynthetic enzyme responsible for the endogenous synthesis of fatty acids. It is downregulated in most normal cells, except in lipogenic tissues such as liver, lactating breast, fetal lung, and adipose tissue. Conversely, several human cancers, including head and neck squamous cell carcinomas (HNSCC), overexpress FASN, which has been associated with poor prognosis and recently suggested as a metabolic oncoprotein. Orlistat is an irreversible inhibitor of FASN activity with cytotoxic properties on several cancer cell lines that inhibits tumor progression and metastasis in prostate cancer xenografts and experimental melanomas, respectively. To explore whether the inhibition of FASN could impact oral tongue squamous cell carcinoma (OTSCC) metastatic spread, an orthotopic model was developed by the implantation of SCC-9 ZsGreen LN-1 cells into the tongue of BALB/c nude mice. These cells were isolated through in vivo selection, show a more invasive behavior in vitro than the parental cells, and generate orthotopic tumors that spontaneously metastasize to cervical lymph nodes in 10 to 15 days only. SCC-9 ZsGreen LN-1 cells also exhibit enhanced production of MMP-2, ERBB2, andCDH2. The treatment with orlistat reduced proliferation and migration, promoted apoptosis, and stimulated the secretion of VEGFA(165b) by SCC-9 ZsGreen LN-1 cells. In vivo, the drug was able to decrease both the volume and proliferation indexes of the tongue orthotopic tumors and, importantly, reduced the number of metastatic cervical lymph nodes by 43%. These results suggest that FASN is a potential molecular target for the chemotherapy of patients with OTSCC. (C)2013 AACR. (AU)

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