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Oncogene (2017) 36, 912921
http://www.nature.com/onc
Web End =www.nature.com/onc
U Harjes1,8,9, E Bridges1,8, KM Gharpure2,8, I Roxanis3, H Sheldon1, F Miranda4, LS Mangala2,5, S Pradeep2, G Lopez-Berestein5,6, A Ahmed4, B Fielding7, AK Sood2,5,6,10 and AL Harris1,10
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
Oncogene (2017) 36, 912921; doi:http://dx.doi.org/10.1038/onc.2016.256
Web End =10.1038/onc.2016.256 ; published online 29 August 2016
INTRODUCTION
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.25 Via the TCA cycle, the oxidation of FAs (FAO) signicantly 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 19 (FABP19). However, 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. FABP4 / adipocytes, in which this feedback inhibition is lost, show higher lipolytic rates and higher levels of intracellular free FAs.7,8 In addition,...