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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BlackWell Publishing Ltd
2014
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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. |
format | Online Article Text |
id | pubmed-4023885 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BlackWell Publishing Ltd |
record_format | MEDLINE/PubMed |
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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