Abstract B110: Brusatol-induced degradation of HIF-1α by inhibiting c-Myc causes colorectal cancer cell death under hypoxia

Abstract

Abstract Hypoxia-inducible factor-1 (HIF-1) regulates the expression of ~100 genes involved in metastasis, tumor growth, angiogenesis, chemoresistance, and radioresistance. Therefore, there is growing interest in targeting HIF-1 for cancer treatment. Here, we investigated the molecular mechanisms underlying brusatol-induced degradation of HIF-1α and colorectal cancer cell death under hypoxia. Brusatol pretreatment enhanced degradation of HIF-1α and increased colorectal cancer cell death under hypoxia. Brusatol activated the prolyl hydroxylases (PHDs), and siRNA-mediated knockdown of PHDs prevented brusatol-induced degradation of HIF-1α and colorectal cancer cell death. Additionally, 2,2’-bypyridyl, a ferrous iron chelator, effectively inhibited brusatol-induced degradation of HIF-1α and colorectal cancer cell death in hypoxia by inhibiting PHD activation. We also found that brusatol inhibited c-Myc expression, and showed that overexpression of c-Myc prevented brusatol-induced degradation of HIF-1α and colorectal cancer cell death by inhibiting mitochondrial ROS generation 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-1α degradation. Collectively, our results suggest that brusatol-mediated inhibition of c-Myc/ROS signaling pathway increases HIF-1α degradation by promoting PHD activity and induces colorectal cancer cell death under hypoxia. Citation Format: Eun-Taex Oh, Chan Woo Kim, Ha Gyeong Kim, Heon Joo Park. Brusatol-induced degradation of HIF-1α by inhibiting c-Myc causes colorectal cancer cell death under hypoxia [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B110.