Molecular Bases of Disease
Terpestacin Inhibits Tumor Angiogenesis by Targeting UQCRB of Mitochondrial Complex III and Suppressing Hypoxia-induced Reactive Oxygen Species Production and Cellular Oxygen Sensing*

https://doi.org/10.1074/jbc.M109.087809Get rights and content
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Cellular oxygen sensing is required for hypoxia-inducible factor-1α stabilization, which is important for tumor cell survival, proliferation, and angiogenesis. Here we find that terpestacin, a small molecule previously identified in a screen of microbial extracts, binds to the 13.4-kDa subunit (UQCRB) of mitochondrial Complex III, resulting in inhibition of hypoxia-induced reactive oxygen species generation. Consequently, such inhibition blocks hypoxia-inducible factor activation and tumor angiogenesis in vivo, without inhibiting mitochondrial respiration. Overexpression of UQCRB or its suppression using RNA interference demonstrates that it plays a crucial role in the oxygen sensing mechanism that regulates responses to hypoxia. These findings provide a novel molecular basis of terpestacin targeting UQCRB of Complex III in selective suppression of tumor progression.

Drug Action
Hypoxia
Mitochondria
Reactive Oxygen Species (ROS)
Tumor Metastases
Electron Transport Chain
Hypoxia-inducible Factor
Terpestacin
Tumor Angiogenesis
UQCRB of Complex III

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*

This work was supported by the National R & D Program for Cancer Control, Ministry of Health & Welfare, the Translational Research Center for Protein Function Control, KRF Grant 2009-0083522, the National Research Foundation of Korea Grant funded by Korean Government Grant 2009-0092964, and the Brain Korea 21 project of the Republic of Korea. This work was supported, in whole or in part, by National Institutes of Health Grants HL35440 and HL079650 (to P. T. S. and P. T. M.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

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Both authors contributed equally to this work.