期刊
ONCOGENE
卷 28, 期 3, 页码 313-324出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.398
关键词
hypoxia-inducible factor-1 alpha; silibinin; cancer; mTOR; angiogenesis
资金
- ISCIII [FIS03-0924, FIS07-1168]
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)
- Spanish Ministry of Health and Consumer Affairs
- Pro-CNIC Foundation
The hypoxia-inducible factor 1 (HIF-1) plays a critical role for tumour adaptation to microenvironmental hypoxia, and represents an appealing chemotherapeutic target. Silibinin is a nontoxic flavonoid reported to exhibit anticancer properties. However, the mechanisms by which silibinin inhibits tumour growth are not fully understood. In this study, silibinin was found to inhibit hypoxiainduced HIF-1 alpha accumulation and HIF-1 transcriptional activity in human cervical (HeLa) and hepatoma (Hep3B) cells. Neither HIEF-1 alpha protein degradation rate nor HIEF-1 alpha steady-state mRNA level was affected by silibinin. Rather, we found that suppression of HIF-1 alpha accumulation by silibinin correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIEF-1 alpha expression at the translational level. Silibinin also activated Akt, a mechanistic feature exhibited by established mTOR inhibitors in many tumour cells. Moreover, silibinin reduced hypoxia-induced vascular endothelial growth factor (VEGF) release by HeLa and Hep3B cells, and this effect was potentiated by the PI3K/Akt inhibitor LY294002. Finally, silibinin was found to be a potent inhibitor of cell proliferation. These results show that silibinin is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据