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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| 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.
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| Authors | 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 |
| Journal | The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 15 Pg. 11584-95 (Apr 09 2010) ISSN: 1083-351X [Electronic] United States |
| PMID | 20145250 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
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