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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

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

Oh Eun-Taex ET Kim Chan Woo CW Kim Ha Gyeong HG Lee Jae-Seon JS Park Heon Joo HJ

Theranostics 20170811 14

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% O<sub>2</sub>). Under hypoxia, pretreatment of cancer cells with brusatol increased HIF-1α degrada ...[more]

PMID: 28912885

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Project description:BackgroundUnder conditions of hypoxia, cancer cells with hypoxia inducible factor-1α (HIF-1α) from heterogeneous tumor cells show greater aggression and progression in an effort to compensate for harsh environmental conditions. Extensive study on the stability of HIF-1α under conditions of acute hypoxia in cancer progression has been conducted, however, understanding of its involvement during the chronic phase is limited.MethodsIn this study, we investigated the effect of SIRT1 on HIF1 stability in a typical chronic hypoxic conditon that maintains cells for 24 h under hypoxia using Western blotting, co-IP, measurement of intracellular NAD + and NADH levels, semi-quantitative RT-PCR analysis, invasion assay, gene knockdown.ResultsHere we demonstrated that the high concentration of pyruvate in the medium, which can be easily overlooked, has an effect on the stability of HIF-1α. We also demonstrated that NADH functions as a signal for conveyance of HIF-1α degradation via the SIRT1 and VHL signaling pathway under conditions of chronic hypoxia, which in turn leads to attenuation of hypoxically strengthened invasion and angiogenic activities. A steep increase in the level of NADH occurs during chronic hypoxia, leading to upregulation of acetylation and degradation of HIF-1α via inactivation of SIRT1. Of particular interest, p300-mediated acetylation at lysine 709 of HIF-1α is recogonized by VHL, which leads to degradation of HIF-1α via ubiquitin/proteasome machinary under conditions of chronic hypoxia. In addition, we demonstrated that NADH-elevation-induced acetylation and subsequent degradation of HIF-1α was independent of proline hydroxylation.ConclusionsOur findings suggest a critical role of SIRT1 as a metabolic sensor in coordination of hypoxic status via regulation of HIF-1α stability. These results also demonstrate the involvement of VHL in degradation of HIF-1α through recognition of PHD-mediated hydroxylation in normoxia and p300-mediated HIF-1α acetylation in hypoxia.

Dataset Information

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

Publications

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

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