Abstract
Fatty acid binding protein 4 (FABP4) is a fatty acid chaperone, which is induced during adipocyte differentiation. Previously we have shown that FABP4 in endothelial cells is induced by the NOTCH1 signalling pathway, the latter of which is involved in mechanisms of resistance to antiangiogenic tumour therapy. Here, we investigated the role of FABP4 in endothelial fatty acid metabolism and tumour angiogenesis. We analysed the effect of transient FABP4 knockdown in human umbilical vein endothelial cells on fatty acid metabolism, viability and angiogenesis. Through therapeutic delivery of siRNA targeting mouse FABP4, we investigated the effect of endothelial FABP4 knockdown on tumour growth and blood vessel formation. In vitro, siRNA-mediated FABP4 knockdown in endothelial cells led to a marked increase of endothelial fatty acid oxidation, an increase of reactive oxygen species and decreased angiogenesis. In vivo, we found that increased NOTCH1 signalling in tumour xenografts led to increased expression of endothelial FABP4 that decreased when NOTCH1 and VEGFA inhibitors were used in combination. Angiogenesis, growth and metastasis in ovarian tumour xenografts were markedly inhibited by therapeutic siRNA delivery targeting mouse endothelial FABP4. Therapeutic targeting of endothelial FABP4 by siRNA in vivo has antiangiogenic and antitumour effects with minimal toxicity and should be investigated further.
Highlights
The metabolism of fatty acids (FA) has been recognized as a key process required for the formation of new blood vessels.[1]
We found that more than 50% of the vessels in Delta-like ligand 4 (DLL4)-overexpressing xenografts showed a strong Fatty acid binding protein 4 (FABP4) expression compared with 10–20% of the vessels in the control tumours (P o 0.00001) (Figures 1a and b)
In tumours treated with bevazicumab (BEV, antibody targeting Vascular endothelial growth factor A (VEGFA)) or dibenzazepine (DBZ, inhibits NOTCH1 signalling by inhibiting γ-secretase), FABP4 staining in the vessels of DLL4-overexpressing tumours was still stronger and more extensive than in the vessels of EV tumours (P o 0.01 in BEV-treated, Po 0.05 in DBZ-treated tumours)
Summary
The metabolism of fatty acids (FA) has been recognized as a key process required for the formation of new blood vessels (angiogenesis).[1] FAs can be used for membrane and lipid synthesis, regulation of gene expression and energy production.[2,3,4,5] Via the TCA cycle, the oxidation of FAs (FAO) significantly contributes to the de novo synthesis of nucleotides during endothelial cell (EC) proliferation.[1] Upon uptake and release of FAs into the cell, FAs are either activated by acyl-CoA synthases or bound by FA-binding proteins 1–9 (FABP1–9). FAs, which are not converted to FA-CoA or bound to FABPs, can cause cellular stress.[6] Adipocyte FABP4 binds FAs and provides feedback inhibition of lipolysis through interaction with lipases. This was linked to reduced utilization of adipocyte-derived FAs in tumour cells and to reduced FABP4 expression in adipocytes and adjacent tumour cells.[11]
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