Effects of pharmacological inhibition of the TE, KS and ER domains of fatty acid synthase (FASN)enzyme on the processes of adhesion, migration and invasion of oral squamous cell carcinoma cells (SCC-9)

• Grant number: 16/24906-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): March 01, 2017
• Effective date (End): August 31, 2018
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Débora Campanella Bastos
• Grantee: Willian Peter Boelcke
• Host Institution: Faculdade de Odontologia de Piracicaba (FOP). Universidade Estadual de Campinas (UNICAMP). Piracicaba , SP, Brazil

Abstract

Fatty acid synthase enzyme (FASN - fatty acid synthase, EC 2.3.1.85) is responsible for the endogenous synthesis of long chain fatty acids by performing condensation reactions of the precursors acetyl-CoA and malonyl-CoA. FASN complex is formed by seven catalytic domains [²-ketoacyl synthase (KS), acetyl-CoA transacylases e malonyl-CoA transacylases (MAT), dehydratase (DH), enoyl reductase (ER), ²-ketoacyl reductase (KR), thioesterase (TE) e acil-carrier protein (ACP], which are sequentially organized in two polypeptidic chains. In several malignant neoplasms, FASN levels are increased and associated with poor prognosis and risk of metastases, including the oral squamous cell carcinoma (SCC). FASN natural or synthetic inhibitors contain antiproliferative and antineoplastic properties. Among them, cerulenin (CER) and its synthetic derivative, C75, which inhibits the KS site, the triclosan antibiotic (TCS) binding to the ER domain, and the antiobesity drug, orlistat (ORL) which inhibits the TE domain of FASN. Previous studies conducted in our laboratory demonstrated that inhibition of FASN with ORL was able to reduce the migration of the SCC cell line, SCC-9 ZsGreen LN-1, a highly aggressive derivative of SCC-9 cells. The in vivo results of this study demonstrated that the treatment with ORL reduced the volume of the orthotropic tumors and the number of cervical lymph nodes metastases. However, the mechanism by which FASN inhibition affects adhesion, migration and invasion of SCC cells is not described in the literature. Thus, the goal of this study is to analyze and compare the pharmacological inhibition of FASN C75, TCS and ORL in SCC-9 cell line on the processes of adhesion, migration and invasion in vitro. (AU)