科研之友
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摘要
Hypoxia-inducible factor-1 (HIF-1) is the central mediator of cellular responses to low oxygen and vital to many aspects of cancer biology. In a search for HIF-1 inhibitors, we identified celastrol as an inhibitor of HIF-1 activation from Tripterygium wilfordii. In the present study, we demonstrated the effect of celastrol on HIF-1 activation. Celastrol showed a potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1 alpha protein dose-dependently, whereas it did not affect the expressions of HIF-1 beta and topoisomerase-I (topo-I). Furthermore, celastrol prevented hypoxia-induced expression of HIF-1 target genes for vascular endothelial growth factor (VEGF) and erythropoietin (EPO). Further analysis revealed that celastrol inhibited HIF-1 alpha protein synthesis, without affecting the expression level of HIF-1 alpha mRNA or degradation of HIF-1 alpha a protein. Markedly, we found that suppression of HIF-1 alpha accumulation by celastrol correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors, ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E (eIF4E) and extracellular signal-regulated kinase (ERK), pathways known to regulate HIF-1 alpha expression at the translational level. In vivo studies further confirmed the inhibitory effect of celastrol on the expression of HIF-1 alpha proteins, leading to a decreased growth of Hep3B cells in a xenograft tumor model. Our data suggested that celastrol is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.
- 出版日期2014-7
- 单位延边大学; 吉林省人民医院
