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Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing

Lookup NU author(s): Dr Satomi Miwa

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

In the normal quiescent vasculature, only 0.01% of endothelial cells (ECs) are proliferating. However, this proportion increases dramatically following the angiogenic switch during tumor growth or wound healing. Recent evidence suggests that this angiogenic switch is accompanied by a metabolic switch. Here, we show that proliferating ECs increasingly depend on mitochondrial oxidative phosphorylation (OxPhos) for their increased energy demand. Under growth conditions, ECs consume three times more oxygen than quiescent ECs and work close to their respiratory limit. The increased utilization of the proton motif force leads to a reduced mitochondrial membrane potential in proliferating ECs and sensitizes to mitochondrial uncoupling. The benzoquinone embelin is a weak mitochondrial uncoupler that prevents neoangiogenesis during tumor growth and wound healing by exhausting the low respiratory reserve of proliferating ECs without adversely affecting quiescent ECs. We demonstrate that this can be exploited therapeutically by attenuating tumor growth in syngenic and xenograft mouse models. This novel metabolic targeting approach might be clinically valuable in controlling pathological neoangiogenesis while sparing normal vasculature and complementing cytostatic drugs in cancer treatment.

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Author(s): Coutelle O, Hornig-Do HT, Witt A, Andree M, Schiffmann LM, Piekarek M, Brinkmann K, Seeger JM, Liwschitz M, Miwa S, Hallek M, Kronke M, Trifunovic A, Eming SA, Wiesner RJ, Hacker UT, Kashkar H

Publication type: Article

Publication status: Published

Journal: EMBO Molecular Medicine

Year: 2014

Volume: 6

Issue: 5

Pages: 624-639

Print publication date: 01/05/2014

Online publication date: 09/03/2014

Acceptance date: 11/02/2014

Date deposited: 03/10/2014

ISSN (print): 1757-4676

ISSN (electronic): 1757-4684

Publisher: Wiley-Blackwell Publishing Ltd.

URL: http://dx.doi.org/10.1002/emmm.201303016

DOI: 10.1002/emmm.201303016

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