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Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma

Drug resistance limits the achievement of persistent cures for the treatment of melanoma, in spite of the efficacy of the available drugs. The aim of the present study was to explore the involvement of lipid metabolism in melanoma resistance and assess the effects of its targeting in cellular models...

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Autores principales: Vergani, Elisabetta, Beretta, Giovanni L., Aloisi, Mariachiara, Costantino, Matteo, Corno, Cristina, Frigerio, Simona, Tinelli, Stella, Dugo, Matteo, Accattatis, Felice Maria, Granata, Agnese, Arnaboldi, Lorenzo, Rodolfo, Monica, Perego, Paola, Gatti, Laura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326082/
https://www.ncbi.nlm.nih.gov/pubmed/35912092
http://dx.doi.org/10.3389/fcell.2022.927118
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author Vergani, Elisabetta
Beretta, Giovanni L.
Aloisi, Mariachiara
Costantino, Matteo
Corno, Cristina
Frigerio, Simona
Tinelli, Stella
Dugo, Matteo
Accattatis, Felice Maria
Granata, Agnese
Arnaboldi, Lorenzo
Rodolfo, Monica
Perego, Paola
Gatti, Laura
author_facet Vergani, Elisabetta
Beretta, Giovanni L.
Aloisi, Mariachiara
Costantino, Matteo
Corno, Cristina
Frigerio, Simona
Tinelli, Stella
Dugo, Matteo
Accattatis, Felice Maria
Granata, Agnese
Arnaboldi, Lorenzo
Rodolfo, Monica
Perego, Paola
Gatti, Laura
author_sort Vergani, Elisabetta
collection PubMed
description Drug resistance limits the achievement of persistent cures for the treatment of melanoma, in spite of the efficacy of the available drugs. The aim of the present study was to explore the involvement of lipid metabolism in melanoma resistance and assess the effects of its targeting in cellular models of melanoma with acquired resistance to the BRAF-inhibitor PLX4032/Vemurafenib. Since transcriptional profiles pointed to decreased cholesterol and fatty acids synthesis in resistant cells as compared to their parental counterparts, we examined lipid composition profiles of resistant cells, studied cell growth dependence on extracellular lipids, assessed the modulation of enzymes controlling the main nodes in lipid biosynthesis, and evaluated the effects of targeting Acetyl-CoA Acetyltransferase 2 (ACAT2), the first enzyme in the cholesterol synthesis pathway, and Acyl-CoA Cholesterol Acyl Transferase (ACAT/SOAT), which catalyzes the intracellular esterification of cholesterol and the formation of cholesteryl esters. We found a different lipid composition in the resistant cells, which displayed reduced saturated fatty acids (SFA), increased monounsaturated (MUFA) and polyunsaturated (PUFA), and reduced cholesteryl esters (CE) and triglycerides (TG), along with modulated expression of enzymes regulating biosynthetic nodes of the lipid metabolism. The effect of tackling lipid metabolism pathways in resistant cells was evidenced by lipid starvation, which reduced cell growth, increased sensitivity to the BRAF-inhibitor PLX4032, and induced the expression of enzymes involved in fatty acid and cholesterol metabolism. Molecular targeting of ACAT2 or pharmacological inhibition of SOAT by avasimibe showed antiproliferative effects in melanoma cell lines and a synergistic drug interaction with PLX4032, an effect associated to increased ferroptosis. Overall, our findings reveal that lipid metabolism affects melanoma sensitivity to BRAF inhibitors and that extracellular lipid availability may influence tumor cell response to treatment, a relevant finding in the frame of personalized therapy. In addition, our results indicate new candidate targets for drug combination treatments.
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spelling pubmed-93260822022-07-28 Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma Vergani, Elisabetta Beretta, Giovanni L. Aloisi, Mariachiara Costantino, Matteo Corno, Cristina Frigerio, Simona Tinelli, Stella Dugo, Matteo Accattatis, Felice Maria Granata, Agnese Arnaboldi, Lorenzo Rodolfo, Monica Perego, Paola Gatti, Laura Front Cell Dev Biol Cell and Developmental Biology Drug resistance limits the achievement of persistent cures for the treatment of melanoma, in spite of the efficacy of the available drugs. The aim of the present study was to explore the involvement of lipid metabolism in melanoma resistance and assess the effects of its targeting in cellular models of melanoma with acquired resistance to the BRAF-inhibitor PLX4032/Vemurafenib. Since transcriptional profiles pointed to decreased cholesterol and fatty acids synthesis in resistant cells as compared to their parental counterparts, we examined lipid composition profiles of resistant cells, studied cell growth dependence on extracellular lipids, assessed the modulation of enzymes controlling the main nodes in lipid biosynthesis, and evaluated the effects of targeting Acetyl-CoA Acetyltransferase 2 (ACAT2), the first enzyme in the cholesterol synthesis pathway, and Acyl-CoA Cholesterol Acyl Transferase (ACAT/SOAT), which catalyzes the intracellular esterification of cholesterol and the formation of cholesteryl esters. We found a different lipid composition in the resistant cells, which displayed reduced saturated fatty acids (SFA), increased monounsaturated (MUFA) and polyunsaturated (PUFA), and reduced cholesteryl esters (CE) and triglycerides (TG), along with modulated expression of enzymes regulating biosynthetic nodes of the lipid metabolism. The effect of tackling lipid metabolism pathways in resistant cells was evidenced by lipid starvation, which reduced cell growth, increased sensitivity to the BRAF-inhibitor PLX4032, and induced the expression of enzymes involved in fatty acid and cholesterol metabolism. Molecular targeting of ACAT2 or pharmacological inhibition of SOAT by avasimibe showed antiproliferative effects in melanoma cell lines and a synergistic drug interaction with PLX4032, an effect associated to increased ferroptosis. Overall, our findings reveal that lipid metabolism affects melanoma sensitivity to BRAF inhibitors and that extracellular lipid availability may influence tumor cell response to treatment, a relevant finding in the frame of personalized therapy. In addition, our results indicate new candidate targets for drug combination treatments. Frontiers Media S.A. 2022-07-13 /pmc/articles/PMC9326082/ /pubmed/35912092 http://dx.doi.org/10.3389/fcell.2022.927118 Text en Copyright © 2022 Vergani, Beretta, Aloisi, Costantino, Corno, Frigerio, Tinelli, Dugo, Accattatis, Granata, Arnaboldi, Rodolfo, Perego and Gatti. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Vergani, Elisabetta
Beretta, Giovanni L.
Aloisi, Mariachiara
Costantino, Matteo
Corno, Cristina
Frigerio, Simona
Tinelli, Stella
Dugo, Matteo
Accattatis, Felice Maria
Granata, Agnese
Arnaboldi, Lorenzo
Rodolfo, Monica
Perego, Paola
Gatti, Laura
Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma
title Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma
title_full Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma
title_fullStr Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma
title_full_unstemmed Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma
title_short Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma
title_sort targeting of the lipid metabolism impairs resistance to braf kinase inhibitor in melanoma
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326082/
https://www.ncbi.nlm.nih.gov/pubmed/35912092
http://dx.doi.org/10.3389/fcell.2022.927118
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