Silibinin inhibits hypoxia-inducible factor-1alpha and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: implications for anticancer therapy.

Abstract:

: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 hypoxia-induced HIF-1alpha accumulation and HIF-1 transcriptional activity in human cervical (HeLa) and hepatoma (Hep3B) cells. Neither HIF-1alpha protein degradation rate nor HIF-1alpha steady-state mRNA level was affected by silibinin. Rather, we found that suppression of HIF-1alpha 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 HIF-1alpha 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.

journal_name

Oncogene

journal_title

Oncogene

authors

García-Maceira P,Mateo J

doi

10.1038/onc.2008.398

subject

Has Abstract

pub_date

2009-01-22 00:00:00

pages

313-24

issue

3

eissn

0950-9232

issn

1476-5594

pii

onc2008398

journal_volume

28

pub_type

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