Cargando…
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...
Autores principales: | , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784757198166949888 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9326082 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT verganielisabetta targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT berettagiovannil targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT aloisimariachiara targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT costantinomatteo targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT cornocristina targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT frigeriosimona targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT tinellistella targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT dugomatteo targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT accattatisfelicemaria targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT granataagnese targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT arnaboldilorenzo targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT rodolfomonica targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT peregopaola targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma AT gattilaura targetingofthelipidmetabolismimpairsresistancetobrafkinaseinhibitorinmelanoma |