terpestacin and Hypoxia

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.

Topics: Animals; Bridged Bicyclo Compounds; Carrier Proteins; Electron Transport Complex III; Endothelium, Vascular; Female; Hypoxia; Mice; Mice, Inbred C3H; Mitochondria; Neoplasm Transplantation; Neovascularization, Pathologic; Oxygen; Reactive Oxygen Species; Vascular Endothelial Growth Factor A