Brusatol-Mediated Inhibition of c-Myc Increases HIF-1? Degradation and Causes Cell Death in Colorectal Cancer under Hypoxia.

ABSTRACT: 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? degradation and cell death in colorectal cancer under hypoxia (0.5% O₂). Under hypoxia, pretreatment of cancer cells with brusatol increased HIF-1? 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? 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? 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? 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? degradation. Collectively, our results suggest that brusatol-mediated inhibition of c-Myc/ROS signaling pathway increases HIF-1? degradation by promoting PHD activity and induces cell death in colorectal cancer under hypoxia.

SUBMITTER: Oh ET 

PROVIDER: S-EPMC5596433 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature