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Cell Metab. 2019 Apr 28. pii: S1550-4131(19)30188-3. doi: 10.1016/j.cmet.2019.04.004. [Epub ahead of print]

Acyl-CoA-Binding Protein Drives Glioblastoma Tumorigenesis by Sustaining Fatty Acid Oxidation.

Author information

1
Department of Clinical Neurobiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
2
Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
3
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
4
Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 220, Heidelberg 69120, Germany.
5
Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, Heidelberg 69120, Germany.
6
Department of Clinical Neurobiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. Electronic address: j.alfonso@dkfz.de.

Abstract

Glioblastoma multiforme (GBM) undergoes metabolic reprogramming to meet the high ATP and anabolic demands of the tumor cells. However, the role of fatty acid oxidation (FAO) and its regulators in the GBM context has been largely unknown. Here, we show that the neural stem cell pro-proliferative factor acyl-CoA-binding protein (ACBP, also known as DBI) is highly expressed in GBM, and by binding to acyl-CoAs, it cell-autonomously maintains high proliferation rates, promoting tumor growth and poor survival in several preclinical models. Mechanistic experiments using ACBP-acyl-CoA binding affinity variants and pharmacological FAO modulators suggest that ACBP supports tumor growth by controlling the availability of long-chain fatty acyl-CoAs to mitochondria, promoting FAO in GBM. Thus, our findings uncover a critical link between lipid metabolism and GBM progression established by ACBP and offer a potential therapeutic strategy for an effective anti-proliferative metabolic management of GBM.

KEYWORDS:

ACBP; DBI; GABA(A) receptor; acyl-CoA; brain cancer; glioblastoma; lipid metabolism; mitochondrial respiration; senescence; β-oxidation

PMID:
31056285
DOI:
10.1016/j.cmet.2019.04.004

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