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

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)11584-11595
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number15
DOIs
Publication statusPublished - 2010 Apr 9

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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