Hye Jin Jung, Joong Sup Shim, Jiyong Lee, Young Mi Song, Ki Chung Park, Seung Hoon Choi, Nam Doo Kim, Jeong Hyeok Yoon, Mungai, Paul T., Schumacker, Paul T., and Ho Jeong Kwon
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. [ABSTRACT FROM AUTHOR]