Coutelle, Oliver, Hornig-Do, Hue-Tran, Witt, Axel, Andree, Maria, Schiffmann, Lars M., Piekarek, Michael, Brinkmann, Kerstin, Seeger, Jens M., Liwschitz, Maxim, Miwa, Satomi ORCID: 0000-0002-1239-1198, Hallek, Michael, Kroenke, Martin, Trifunovic, Aleksandra, Eming, Sabine A., Wiesner, Rudolf J., Hacker, Ulrich T. and Kashkar, Hamid (2014). Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing. EMBO Mol. Med., 6 (5). S. 624 - 640. HOBOKEN: WILEY. ISSN 1757-4684

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Coutelle, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hornig-Do, Hue-TranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witt, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andree, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schiffmann, Lars M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piekarek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkmann, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger, Jens M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liwschitz, MaximUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miwa, SatomiUNSPECIFIEDorcid.org/0000-0002-1239-1198UNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroenke, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trifunovic, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eming, Sabine A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiesner, Rudolf J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hacker, Ulrich T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-438899
DOI: 10.1002/emmm.201303016
Journal or Publication Title: EMBO Mol. Med.
Volume: 6
Number: 5
Page Range: S. 624 - 640
Date: 2014
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1757-4684
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FATTY-ACID OXIDATION; CELL PROLIFERATION; METABOLISM; GLYCOLYSIS; MUTATIONS; PROTEIN; PHOSPHORYLATION; TRANSDUCTION; ANGIOGENESIS; CONTRIBUTESMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43889

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