Terpestacin Inhibits Tumor Angiogenesis by Targeting UQCRB of Mitochondrial Complex III and Suppressing Hypoxia-induced Reactive Oxygen Species Production and Cellular Oxygen Sensing
Terpestacin Inhibits Tumor Angiogenesis by Targeting UQCRB of Mitochondrial Complex III and Suppressing Hypoxia-induced Reactive Oxygen Species Production and Cellular Oxygen Sensing
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DOI：
10.1074/jbc.m109.087809
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发表时间：
2010-04-09
影响因子：
4.8
通讯作者：
Kwon, Ho Jeong
中科院分区：
文献类型：
--
作者：
Jung, Hye Jin;Shim, Joong Sup;Kwon, Ho Jeong
细胞氧感知是缺氧诱导因子-1 α稳定所必需的，这对肿瘤细胞存活、增殖和血管生成非常重要。本研究发现，先前在微生物提取物筛选中发现的一种小分子terpestacin与线粒体复合物III的13.4 kda亚基（UQCRB）结合，从而抑制缺氧诱导的活性氧生成。因此，这种抑制抑制了体内缺氧诱导因子的激活和肿瘤血管生成，而不抑制线粒体呼吸。UQCRB的过表达或通过RNA干扰抑制表明，它在调节缺氧反应的氧传感机制中起着至关重要的作用。这些发现为terpestacin靶向复合物III的UQCRB选择性抑制肿瘤进展提供了新的分子基础。
Cellular oxygen sensing is required for hypoxia-inducible factor-1 alpha 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.