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Targeting fatty acid oxidation via Acyl-CoA binding protein hinders glioblastoma invasion

The diffuse nature of Glioblastoma (GBM) tumors poses a challenge to current therapeutic options. We have previously shown that Acyl-CoA Binding Protein (ACBP, also known as DBI) regulates lipid metabolism in GBM cells, favoring fatty acid oxidation (FAO). Here we show that ACBP downregulation resul...

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Autores principales: Duman, Ceren, Di Marco, Barbara, Nevedomskaya, Ekaterina, Ulug, Berk, Lesche, Ralf, Christian, Sven, Alfonso, Julieta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10148872/
https://www.ncbi.nlm.nih.gov/pubmed/37120445
http://dx.doi.org/10.1038/s41419-023-05813-0
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author Duman, Ceren
Di Marco, Barbara
Nevedomskaya, Ekaterina
Ulug, Berk
Lesche, Ralf
Christian, Sven
Alfonso, Julieta
author_facet Duman, Ceren
Di Marco, Barbara
Nevedomskaya, Ekaterina
Ulug, Berk
Lesche, Ralf
Christian, Sven
Alfonso, Julieta
author_sort Duman, Ceren
collection PubMed
description The diffuse nature of Glioblastoma (GBM) tumors poses a challenge to current therapeutic options. We have previously shown that Acyl-CoA Binding Protein (ACBP, also known as DBI) regulates lipid metabolism in GBM cells, favoring fatty acid oxidation (FAO). Here we show that ACBP downregulation results in wide transcriptional changes affecting invasion-related genes. In vivo experiments using patient-derived xenografts combined with in vitro models demonstrated that ACBP sustains GBM invasion via binding to fatty acyl-CoAs. Blocking FAO mimics ACBP(KD)-induced immobility, a cellular phenotype that can be rescued by increasing FAO rates. Further investigation into ACBP-downstream pathways served to identify Integrin beta-1, a gene downregulated upon inhibition of either ACBP expression or FAO rates, as a mediator for ACBP’s role in GBM invasion. Altogether, our findings highlight a role for FAO in GBM invasion and reveal ACBP as a therapeutic vulnerability to stall FAO and subsequent cell invasion in GBM tumors. [Image: see text]
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spelling pubmed-101488722023-05-01 Targeting fatty acid oxidation via Acyl-CoA binding protein hinders glioblastoma invasion Duman, Ceren Di Marco, Barbara Nevedomskaya, Ekaterina Ulug, Berk Lesche, Ralf Christian, Sven Alfonso, Julieta Cell Death Dis Article The diffuse nature of Glioblastoma (GBM) tumors poses a challenge to current therapeutic options. We have previously shown that Acyl-CoA Binding Protein (ACBP, also known as DBI) regulates lipid metabolism in GBM cells, favoring fatty acid oxidation (FAO). Here we show that ACBP downregulation results in wide transcriptional changes affecting invasion-related genes. In vivo experiments using patient-derived xenografts combined with in vitro models demonstrated that ACBP sustains GBM invasion via binding to fatty acyl-CoAs. Blocking FAO mimics ACBP(KD)-induced immobility, a cellular phenotype that can be rescued by increasing FAO rates. Further investigation into ACBP-downstream pathways served to identify Integrin beta-1, a gene downregulated upon inhibition of either ACBP expression or FAO rates, as a mediator for ACBP’s role in GBM invasion. Altogether, our findings highlight a role for FAO in GBM invasion and reveal ACBP as a therapeutic vulnerability to stall FAO and subsequent cell invasion in GBM tumors. [Image: see text] Nature Publishing Group UK 2023-04-29 /pmc/articles/PMC10148872/ /pubmed/37120445 http://dx.doi.org/10.1038/s41419-023-05813-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Duman, Ceren
Di Marco, Barbara
Nevedomskaya, Ekaterina
Ulug, Berk
Lesche, Ralf
Christian, Sven
Alfonso, Julieta
Targeting fatty acid oxidation via Acyl-CoA binding protein hinders glioblastoma invasion
title Targeting fatty acid oxidation via Acyl-CoA binding protein hinders glioblastoma invasion
title_full Targeting fatty acid oxidation via Acyl-CoA binding protein hinders glioblastoma invasion
title_fullStr Targeting fatty acid oxidation via Acyl-CoA binding protein hinders glioblastoma invasion
title_full_unstemmed Targeting fatty acid oxidation via Acyl-CoA binding protein hinders glioblastoma invasion
title_short Targeting fatty acid oxidation via Acyl-CoA binding protein hinders glioblastoma invasion
title_sort targeting fatty acid oxidation via acyl-coa binding protein hinders glioblastoma invasion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10148872/
https://www.ncbi.nlm.nih.gov/pubmed/37120445
http://dx.doi.org/10.1038/s41419-023-05813-0
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