Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells.
Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells.
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Brusatol 抑制 HCT116 细胞缺氧条件下 HIF-1 信号通路并抑制葡萄糖摄取
DOI：
10.1038/srep39123
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发表时间：
2016-12-16
影响因子：
4.6
通讯作者：
Zhu L
中科院分区：
文献类型：
--
作者：
Lu Y;Wang B;Shi Q;Wang X;Wang D;Zhu L
低氧诱导因子-1(HIF-1)是一种重要的转录因子，可诱导人类癌症在低氧条件下的适应性反应，并引发常规治疗的不良预后。在本研究中，我们首次发现从鸦胆子酯中提取的四氢胡萝卜素(Bru)具有抑制HIF-1信号通路的能力。我们发现，在低氧或CoCl2诱导的模拟低氧条件下，Bru浓度依赖地下调HCT116细胞中HIF-1α的蛋白水平，而不会造成明显的细胞毒性。此外，Bru抑制缺氧条件下HIF-1的反式激活活性，抑制HIF-1靶基因的表达，包括血管内皮生长因子、GLUT1、HK2和LDHA。此外，Bru还可通过抑制HIF-1信号通路减少低氧下的葡萄糖消耗。进一步研究表明，Bru对HIF-1信号通路的抑制作用可能与促进HIF-1α降解有关。有趣的是，Bru处理后细胞内ROS水平和线粒体ROS水平均下降，表明线粒体ROS调控参与了Bru的作用。综上所述，这些结果为Bru介导的HIF-1α调控提供了明确的证据，并暗示了其在结肠肿瘤中的治疗潜力。
Hypoxia-inducible factor-1 (HIF-1) is an important transcription factor that induces adaptive responses upon low oxygen conditions in human cancers and triggers off a poor prognostic outcome of conventional treatments. In this study, we discovered for the first time that brusatol (BRU), a quassinoid extracted from Brucea Esters, has the capability to inhibit HIF-1 signaling pathway. We found that BRU concentration-dependently down-regulated HIF-1α protein levels under hypoxia or CoCl2-induced mimic hypoxia in HCT116 cells without causing significant cytotoxicity. Besides, the transactivation activity of HIF-1 was suppressed by BRU under hypoxic conditions, as well as the expression of HIF-1 target genes, including VEGF, GLUT1, HK2 and LDHA. In addition, BRU can also decrease glucose consumption under hypoxia through inhibition of HIF-1 signaling pathway. Further studies revealed that the inhibitory effect of BRU on HIF-1 signaling pathway might be attributed to promoting degradation of HIF-1α. Interestingly, intracellular reactive oxygen species (ROS) levels and mitochondrial ROS level were both decreased by BRU treatment, indicating the involvment of mitochondrial ROS regulation in the action of BRU. Taken together, these results provided clear evidence for BRU-mediated HIF-1α regulation and suggested its therapeutic potential in colon tumors.
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影响因子：
11.5
作者：
Meijer, Tineke W. H.;Kaanders, Johannes H. A. M.;Bussink, Johan
通讯作者：
Bussink, Johan
影响因子：
5.3
作者：
Chan, DA;Sutphin, PD;Giaccia, AJ
通讯作者：
Giaccia, AJ
影响因子：
4
作者：
Hu, Yaozhong;Liu, Jing;Huang, He
通讯作者：
Huang, He
影响因子：
3.5
作者：
Olson, Eric;Demopoulos, Laura;Hiatt, William R.
通讯作者：
Hiatt, William R.
DOI：
10.1073/pnas.95.20.11715
发表时间：
1998-09-29
影响因子：
11.1
作者：
Chandel, NS;Maltepe, E;Schumacker, PT
通讯作者：
Schumacker, PT