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

Abstract

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 ACBPKD-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.

Proteomics-based Model for Predicting the Risk of Brain Metastasis in Patients with Resected Lung Adenocarcinoma carrying the EGFR Mutation

“…The proteins up-regulated in the tumors in the BM group compared with the LR and ODM groups were enriched in the same GO term related to lipid metabolic process, indicating that up-regulation of lipid metabolic pathways, including fatty acid synthesis and oxidation (FAO), may be closely associated with BM recurrence. It has been found that the primary brain tumor glioblastoma multiforme relies on FAO for proliferation and that activation of FAO is achieved by high expression of acyl-CoA binding proteins or fatty acid oxidation enzymes [21,22]. Recently, it has been reported that fatty acid synthesis is increased in HER2+ breast cancer tumors growing in the brain versus extracranial sites [23].…”

Metabolic Profiles Point Out Metabolic Pathways Pivotal in Two Glioblastoma (GBM) Cell Lines, U251 and U-87MG

“…Regarding fatty acid metabolism, pharmacological inhibition of SCD and FADS2 in GBM cells induced palmitate accumulation, which, in combination with TMZ, increased cell death [80]. Moreover, Duman and colleagues showed that blocking fatty acid oxidation through acyl-CoA binding protein induced immobility [81], which is very relevant since invasion is one of the major characteristics of these tumors. Additionally, targeting fatty acid oxidation reduces energy production and cell proliferation [37].…”