Journal
ONCOGENE
Volume 28, Issue 3, Pages 313-324Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.398
Keywords
hypoxia-inducible factor-1 alpha; silibinin; cancer; mTOR; angiogenesis
Funding
- ISCIII [FIS03-0924, FIS07-1168]
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)
- Spanish Ministry of Health and Consumer Affairs
- Pro-CNIC Foundation
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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.
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