Effects of fatty acid synthase inhibitors on lymphatic vessels: an in vitro and in vivo study in a melanoma model

Author(s)

Bastos, Debora C. ; Paupert, Jenny ; Maillard, Catherine ; Seguin, Fabiana ; Carvalho, Marco A. ; Agostini, Michelle ; Coletta, Ricardo D. ; Noel, Agnes ; Graner, Edgard

• Document type: Journal article
• Source: LABORATORY INVESTIGATION; v. 97, n. 2, p. 194-206, FEB 2017.
• Web of Science Citations: 10

Abstract

Fatty acid synthase (FASN) is responsible for the endogenous production of fatty acids from acetyl-CoA and malonyl-CoA. Its overexpression is associated with poor prognosis in human cancers including melanomas. Our group has previously shown that the inhibition of FASN with orlistat reduces spontaneous lymphatic metastasis in experimental B16-F10 melanomas, which is a consequence, at least in part, of the reduction of proliferation and induction of apoptosis. Here, we sought to investigate the effects of pharmacological FASN inhibition on lymphatic vessels by using cell culture and mouse models. The effects of FASN inhibitors cerulenin and orlistat on the proliferation, apoptosis, and migration of human lymphatic endothelial cells (HDLEC) were evaluated with in vitro models. The lymphatic outgrowth was evaluated by using a murine ex vivo assay. B16-F10 melanomas and surgical wounds were produced in the ears of C57BI/6 and Balb-C mice, respectively, and their peripheral lymphatic vessels evaluated by fluorescent microlymphangiography. The secretion of vascular endothelial growth factor C and D (VEGF-C and-D) by melanoma cells was evaluated by ELISA and conditioned media used to study in vitro lymphangiogenesis. Here, we show that cerulenin and orlistat decrease the viability, proliferation, and migration of HDLEC cells. The volume of lymph node metastases from B16-F10 experimental melanomas was reduced by 39% in orlistat-treated animals as well as the expression of VEGF-C in these tissues. In addition, lymphatic vessels from orlistat-treated mice drained more efficiently the injected FITC-dextran. Orlistat and cerulenin reduced VEGF-C secretion and, increase production of VEGF-D by B16-F10 and SK-Mel-25 melanoma cells. Finally, reduced lymphatic cell extensions, were observed following the treatment with conditioned medium from cerulenin- and orlistat-treated B16-F10 cells. Altogether, our results show that FASN inhibitors have anti-metastatic effects by acting on lymphatic endothelium and melanoma cells regardless the increase of lymphatic permeability promoted by orlistat. (AU)

• FAPESP's process: 08/57471-7 - The role of fatty acid synthase activity in apoptosis, metastasis and vasculogenesis in melanoma
• Grantee: Edgard Graner
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/20832-3 - The association of Orlistat with chemotherapic agents for the treatment of oral squamous cell carcinoma: an in vitro and in vivo study in orthotopic models
• Grantee: Edgard Graner
• Support Opportunities: Regular Research Grants
• FAPESP's process: 10/51090-1 - Evaluation of the biological role of fatty acid synthase (FASN) enzyme in lymphatic endothelial cells stimulated by malignant cells in culture
• Grantee: Débora Campanella Bastos
• Support Opportunities: Scholarships in Brazil - Doctorate