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Brusatol-Mediated Inhibition of c-Myc Increases HIF-1α Degradation and Causes Cell Death in Colorectal Cancer Under Hypoxia

Brusatol-Mediated Inhibition of c-Myc Increases HIF-1α Degradation and Causes Cell Death in Colorectal Cancer Under Hypoxia

Eun-Taex Oh, Chan Woo Kim, Ha Gyeong Kim, Jae-Seon Lee, Heon Joo Park

Theranostics. 2017 Aug 11;7(14):3415-3431.

PMID: 28912885

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-1α degradation and cell death in colorectal cancer under hypoxia (0.5% O2). Under hypoxia, pretreatment of cancer cells with brusatol increased HIF-1α 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-1α 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-1α 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-1α 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-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 cell death in colorectal cancer under hypoxia.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP14907983	Brusatol		14907-98-3	Price

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