Terpestacin inhibits tumor angiogenesis by targeting UQCRB of mitochondrial complex III and suppressing hypoxia-induced reactive oxygen species production and cellular oxygen sensing.
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.
Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Hye Jin
HJ
Jung
Joong Sup
JS
Shim
Jiyong
J
Lee
Young Mi
YM
Song
Ki Chung
KC
Park
Seung Hoon
SH
Choi
Nam Doo
ND
Kim
Jeong Hyeok
JH
Yoon
Paul T
PT
Mungai
Paul T
PT
Schumacker
Ho Jeong
HJ
Kwon
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D000860:Hypoxia; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000378:metabolism*; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D001643:Bridged Bicyclo Compounds; D002352:Carrier Proteins; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C027208:ubiquinone-binding proteins; C080890:terpestacin; D014450:Electron Transport Complex III; D010100:Oxygen