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The role of fatty acid synthase activity in apoptosis, metastasis and vasculogenesis in melanoma

Abstract

Fatty acid synthase (FASN) is the enzyme responsible for the endogenous synthesis 01 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 poor prognosis and depth of invasion. We have recently shown a 50% inhibition of spontaneous Iymph node metastases in a mouse melanoma model (B 16-F10 cells/C57BL6 mice) by the treatment with Orlistat. This drug also promoted apoptosis and reduced the proliferation of cultured B 16-F10 cells. In the present research project we propose to extend these observations by investigating; 1) the role o FASN in the cell cycle control of human and mouse melanoma cells; 2) the possible mitochondrial involvement as well as the activated pathways in the apoptotic cell death induced by FASN inhibition with Orlistat or cerulenin; 3) the apoptotic rates of primary human melanoma cell cultures after FASN inhibition and their correlation with clinical and pathological characteristics of each clinical case; 4) the role of FASN in the proliferation of blood and Iymphatic endothelial cells: 5) the mRNA and protein levels as well as the proteasomal degradation 01 the transcription factor HIF1 a following FASN blockage; 6) the effect of Orlistat in the B 16- F10 melanoma-induced angiogenesis; 7) the production of FASN, VEGFR-2/-3, VEGF A/C, and HIF1 a in experimental melanomas treated with FASN inhibitors; 8) the effects of FASN inhibition in the B 16-F10 tumor-induced Iymphangiogenesis by fluorescent microlymphangiography; 9) the role of FASN in lung experimental metastases promoted by the injection of B 16-F1 O cells in the tail vein of C57BL6 mice; 10) the effects of Orlistat and cerulenin in the integrin expression and matrix metalloproteinases (MMPs) -2 and -9 expression/activity in cultured melanoma cells: 11) the expression of integrins and MMPs in experimental abdominal primary melanomas and their mediastinal Iymph node metastases; and finally 12) the role of FASN in the interaction of melanoma cells with macromolecules of the extracellular matrix (Iaminin, fibronectin, and vitronectin). (AU)

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Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE ALMEIDA, LUCIANA Y.; MARIANO, FLAVIA S.; BASTOS, DEBORA C.; CAVASSANI, KAREN A.; RAPHELSON, JANNA; MARIANO, VANIA S.; AGOSTINI, MICHELLE; MOREIRA, FERNANDA S.; COLETTA, RICARDO D.; MATTOS-GRANER, RENATA O.; GRANER, EDGARD. The antimetastatic activity of orlistat is accompanied by an antitumoral immune response in mouse melanoma. Cancer Chemotherapy and Pharmacology, v. 85, n. 2 DEC 2019. Web of Science Citations: 0.
BASTOS, DEBORA C.; PAUPERT, JENNY; MAILLARD, CATHERINE; SEGUIN, FABIANA; CARVALHO, MARCO A.; AGOSTINI, MICHELLE; COLETTA, RICARDO D.; NOEL, AGNES; GRANER, EDGARD. Effects of fatty acid synthase inhibitors on lymphatic vessels: an in vitro and in vivo study in a melanoma model. LABORATORY INVESTIGATION, v. 97, n. 2, p. 194-206, FEB 2017. Web of Science Citations: 10.
AGOSTINI, MICHELLE; ALMEIDA, LUCIANA Y.; BASTOS, DEBORA C.; ORTEGA, ROSE M.; MOREIRA, FERNANDA S.; SEGUIN, FABIANA; ZECCHIN, KARINA G.; RAPOSO, HELENA F.; OLIVEIRA, HELENA C. F.; AMOEDO, NIVEA D.; SALO, TUULA; COLETTA, RICARDO D.; GRANER, EDGARD. The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas. MOLECULAR CANCER THERAPEUTICS, v. 13, n. 3, p. 585-595, MAR 2014. Web of Science Citations: 44.
SEGUIN, F.; CARVALHO, M. A.; BASTOS, D. C.; AGOSTINI, M.; ZECCHIN, K. G.; ALVAREZ-FLORES, M. P.; CHUDZINSKI-TAVASSI, A. M.; COLETTA, R. D.; GRANER, E. The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas. BRITISH JOURNAL OF CANCER, v. 107, n. 6, p. 977-987, SEP 4 2012. Web of Science Citations: 63.
ZECCHIN, KARINA G.; ALBERICI, LUCIANE C.; RICCIO, MARIA FRANCESCA; EBERLIN, MARCOS N.; VERCESI, ANIBAL E.; GRANER, EDGARD; CATHARINO, RODRIGO R. Visualizing inhibition of fatty acid synthase through mass spectrometric analysis of mitochondria from melanoma cells. RAPID COMMUNICATIONS IN MASS SPECTROMETRY, v. 25, n. 3, p. 449-452, FEB 2011. Web of Science Citations: 4.
ZECCHIN, KARINA G.; ROSSATO, FRANCO A.; RAPOSO, HELENA F.; MELO, DANIELA R.; ALBERICI, LUCIANE C.; OLIVEIRA, HELENA C. F.; CASTILHO, ROGER F.; COLETTA, RICARDO D.; VERCESI, ANIBAL E.; GRANER, EDGARD. Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis. LABORATORY INVESTIGATION, v. 91, n. 2, p. 232-240, 2010. Web of Science Citations: 41.

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