Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1.

Céline A Schoonjans,Olivier Feron,Nicolas Joudiou,Luca X Zampieri,Bernard Gallez,Barbara Mathieu,Davide Brusa,Pierre Sonveaux

doi:10.3390/jcm9103308

Abstract

Targeting endothelial cell (EC) metabolism should impair angiogenesis, regardless of how many angiogenic signals are present. The dependency of proliferating ECs on glucose and glutamine for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer. The aim of the present study was to investigate the role of pyruvate dehydrogenase kinase (PDK) inhibition with dichloroacetate (DCA), alone or in combination with the glutaminase-1 (GLS-1) inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), on Human umbilical vein endothelial cells (HUVECs) metabolism, proliferation, apoptosis, migration, and vessel formation. We demonstrated that both drugs normalize HUVECs metabolism by decreasing glycolysis for DCA and by reducing glutamate production for BPTES. DCA and BPTES reduced HUVECs proliferation and migration but have no impact on tube formation. While DCA increased HUVECs respiration, BPTES decreased it. Using both drugs in combination further reduced HUVECs proliferation while normalizing respiration and apoptosis induction. Overall, we demonstrated that DCA, a metabolic drug under study to target cancer cells metabolism, also affects tumor angiogenesis. Combining DCA and BPTES may reduce adverse effect of each drug alone and favor tumor angiogenesis normalization.

Highlights

Once activated by pro-angiogenic factors, endothelial cells (ECs) sprout to extend the vasculature and to supply the growing tumors with oxygen and nutrients [1]
We determined that DCA at 5 mM was the lowest DCA concentration that induces a significant decrease in Human umbilical vein endothelial cells (HUVECs) proliferation
We measured that these effects observed on HUVECs proliferation were associated to pyruvate dehydrogenase kinase (PDK) inhibition, i.e., to a reduction in phosphorylated pyruvate dehydrogenase (PDH)

Summary

Introduction

Once activated by pro-angiogenic factors, endothelial cells (ECs) sprout to extend the vasculature and to supply the growing tumors with oxygen and nutrients [1]. Targeting EC metabolism should impair angiogenesis, regardless of how many angiogenic signals are present [1] The dependency of proliferating ECs on glucose and glutamine and fatty acids for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer [3,4,5]. Glutamine is metabolized into glutamate through glutaminase-1 (GLS-1), which can fuel the mitochondrial tricarboxylic acid (TCA) cycle [5,7,8]. Counteracting glycolysis and glutamine pathways are promising approaches to reduce angiogenesis. In this respect, it has been previously shown that blockade of the glycolytic activator PFKFB3 reduced cancer cell invasion, intravasation, and metastasis by normalizing tumor vessels [6]. It has been shown that the inhibition of GLS-1 impaired ECs survival, proliferation, and migration [5,7,8,9]

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