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

Hye Jin Jung,Joong Sup Shim,Jiyong Lee,Young Mi Song,Ki Chung Park,Seung Hoon Choi,Nam Doo Kim,Jeong Hyeok Yoon,Paul T Mungai,Paul T Schumacker,Ho Jeong Kwon

doi:10.1074/jbc.m109.087809

Hye Jin Jung, Joong Sup Shim + Show 9 more

Open Access

https://doi.org/10.1074/jbc.m109.087809

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Abstract

Cellular oxygen sensing is required for hypoxia-inducible factor-1alpha 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.

Highlights

Sufficient to trigger HIF-1␣ stabilization during hypoxia, and cells lacking mitochondrial DNA and electron transport activity (␳␱ cells) fail to exhibit increased reactive oxygen species (ROS) or up-regulation of HIF-1␣ target genes during hypoxia [3,4,5]
This study provides new insight into the oxygen sensing role of UQCRB in mitochondrial Complex III, and a small molecule targeting that system provides a powerful tool for regulating tumor angiogenesis
The present study reveals a novel role of UQCRB of the mitochondrial

Summary

Introduction

Sufficient to trigger HIF-1␣ stabilization during hypoxia, and cells lacking mitochondrial DNA and electron transport activity (␳␱ cells) fail to exhibit increased ROS or up-regulation of HIF-1␣ target genes during hypoxia [3,4,5]. Confocal microscopy analysis using ter-coumarin and a mitochondrial specific marker, MitoTracker, revealed the fluorescence signal of tercoumarin coincided exactly with that of MitoTracker (Fig. 2C, lower panels), implying again that terpestacin binds to mitochondria in the cells where its target, UQCRB, is located.

Results

Conclusion