%0 Journal Article
%T Brusatol-Mediated Inhibition of c-Myc Increases HIF-1¦Á Degradation and Causes Cell Death in Colorectal Cancer under Hypoxia
%A Chan Woo Kim
%A Eun-Taex Oh
%A Ha Gyeong Kim
%A Heon Joo Park
%A Jae-Seon Lee
%J Theranostics
%D 2017
%I Ivyspring International Publisher
%R 10.7150/thno.20861
%X HIF-1 (hypoxia-inducible factor-1) regulates the expression of ~100 genes involved in angiogenesis, metastasis, tumor growth, chemoresistance and radioresistance, underscoring the growing interest in targeting HIF-1 for cancer control. In the present study, we investigated the molecular mechanisms underlying brusatol-induced HIF-1¦Á degradation and cell death in colorectal cancer under hypoxia (0.5% O2). Under hypoxia, pretreatment of cancer cells with brusatol increased HIF-1¦Á degradation and cancer cell death in a dose-dependent manner. This effect was mediated by activation of prolyl hydroxylases (PHDs), as evidenced by the block of brusatol-induced HIF-1¦Á degradation and cancer cell death by both pharmacological inhibition and siRNA-mediated knockdown of PHDs. In addition, a ferrous iron chelator (2,2'-bypyridyl) blocked brusatol-induced degradation of HIF-1¦Á and cancer cell death in hypoxia by inhibiting PHD activation. We further found that brusatol inhibited c-Myc expression, and showed that overexpression of c-Myc prevented brusatol-induced degradation of HIF-1¦Á and cancer cell death by increasing mitochondrial ROS production and subsequent ROS-mediated transition of ferrous iron to ferric iron. Consistent with these results, treatment of tumor-bearing mice with brusatol significantly suppressed tumor growth by promoting PHD-mediated HIF-1¦Á degradation. Collectively, our results suggest that brusatol-mediated inhibition of c-Myc/ROS signaling pathway increases HIF-1¦Á degradation by promoting PHD activity and induces cell death in colorectal cancer under hypoxia
%K Brusatol
%K Cell death
%K Colorectal cancer
%K HIF-1¦Á
%K Hypoxia.
%U http://www.thno.org/v07p3415.htm