Effects of inhibition of the fatty acid synthase enzyme by nanoencapsulated compounds and overexpression of catalytic mutants on the malignant phenotype of oral squamous cell carcinoma cells

• Grant number: 23/14816-4
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2024
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Débora Campanella Bastos
• Grantee: Débora Campanella Bastos
• Host Institution: Faculdade São Leopoldo Mandic (SLMANDIC). Sociedade Regional de Ensino e Saúde S/S Ltda (SRES). Campinas , SP, Brazil
• Associated researchers: Edgard Graner

Abstract

The fatty acid synthase enzyme (FASN, E.C. 2.3.1.85) is responsible for endogenous synthesis of fatty acids, especially palmitate, from acetyl-CoA and malonyl-CoA. FASN is overexpressed in several human malignancies, including oral squamous cell carcinoma (OSCC), in which is also associated with the worse prognosis. FASN structure contains two polypeptide chains (H 270 kDa each) containing seven distinct catalytic sites, sequentially organized from the N-terminal: ²-ketoacyl synthase (KS), acetyl-malonyl transacylase (MAT), dehydratase (DH), enoyl reductase (ER), ²-ketoacyl reductase (KR), thioesterase (TE) and acyl carrier protein (ACP). The transcriptional or post-translational FASN inhibition using siRNA or pharmacological compound, respectively, is well described to induce antitumor and antiproliferative activities in both, in vitro and in vivo. We have previously demonstrated in OSCC cells that the FASN inhibitor TCS (allosteric inhibitor of ER domain) showed improved effects in comparison with others FASN inhibitors in the malignant phenotype. However, the pharmacological blockade of different FASN domains has been shown to interfere in different metabolic pathways on tumor cells and differentially modulate malignant phenotypes. It is still unclear whether these different effects are due the inhibition of different catalytic domains or are promoted by pharmacological properties not associated with endogenous palmitate production. Thus, the aim of this project is to provide data for the better understanding of the pharmacological and specific inhibition of FASN by 2 different strategies. First, is to improve the therapeutic index of TCS by nanoencapsulation in nanostructured lipid carriers. Second, is to investigate comparatively the specific inhibition of FASN domains through the caracterization of inactive catalitic mutants of the domains KS, ER and TE of FASN in OSCC cell line. (AU)