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

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 switc...

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Autores principales: Coutelle, Oliver, Hornig-Do, Hue-Tran, Witt, Axel, Andree, Maria, Schiffmann, Lars M, Piekarek, Michael, Brinkmann, Kerstin, Seeger, Jens M, Liwschitz, Maxim, Miwa, Satomi, Hallek, Michael, Krönke, Martin, Trifunovic, Aleksandra, Eming, Sabine A, Wiesner, Rudolf J, Hacker, Ulrich T, Kashkar, Hamid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023885/
https://www.ncbi.nlm.nih.gov/pubmed/24648500
http://dx.doi.org/10.1002/emmm.201303016
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author Coutelle, Oliver
Hornig-Do, Hue-Tran
Witt, Axel
Andree, Maria
Schiffmann, Lars M
Piekarek, Michael
Brinkmann, Kerstin
Seeger, Jens M
Liwschitz, Maxim
Miwa, Satomi
Hallek, Michael
Krönke, Martin
Trifunovic, Aleksandra
Eming, Sabine A
Wiesner, Rudolf J
Hacker, Ulrich T
Kashkar, Hamid
author_facet Coutelle, Oliver
Hornig-Do, Hue-Tran
Witt, Axel
Andree, Maria
Schiffmann, Lars M
Piekarek, Michael
Brinkmann, Kerstin
Seeger, Jens M
Liwschitz, Maxim
Miwa, Satomi
Hallek, Michael
Krönke, Martin
Trifunovic, Aleksandra
Eming, Sabine A
Wiesner, Rudolf J
Hacker, Ulrich T
Kashkar, Hamid
author_sort Coutelle, Oliver
collection PubMed
description 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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spelling pubmed-40238852014-05-22 Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing Coutelle, Oliver Hornig-Do, Hue-Tran Witt, Axel Andree, Maria Schiffmann, Lars M Piekarek, Michael Brinkmann, Kerstin Seeger, Jens M Liwschitz, Maxim Miwa, Satomi Hallek, Michael Krönke, Martin Trifunovic, Aleksandra Eming, Sabine A Wiesner, Rudolf J Hacker, Ulrich T Kashkar, Hamid EMBO Mol Med Research Articles 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. BlackWell Publishing Ltd 2014-05 2014-03-20 /pmc/articles/PMC4023885/ /pubmed/24648500 http://dx.doi.org/10.1002/emmm.201303016 Text en © 2014 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Coutelle, Oliver
Hornig-Do, Hue-Tran
Witt, Axel
Andree, Maria
Schiffmann, Lars M
Piekarek, Michael
Brinkmann, Kerstin
Seeger, Jens M
Liwschitz, Maxim
Miwa, Satomi
Hallek, Michael
Krönke, Martin
Trifunovic, Aleksandra
Eming, Sabine A
Wiesner, Rudolf J
Hacker, Ulrich T
Kashkar, Hamid
Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing
title Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing
title_full Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing
title_fullStr Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing
title_full_unstemmed Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing
title_short Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing
title_sort embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023885/
https://www.ncbi.nlm.nih.gov/pubmed/24648500
http://dx.doi.org/10.1002/emmm.201303016
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