Effects of red ginseng extracts on HIF-1α-mediated cellular responses to hypoxia

Abstract

Water extract of Korean red ginseng (KRGW) contains numerous bioactive ginsenosides and is very popularly used as a multi-purpose medicine for health improvement. KRGW has been in the limelight because of its clinical benefit in cancer control. A growing body of evidence suggests that HIF-1 plays critical roles in tumor promotion under hypoxia and that it is a most compelling target for cancer therapy. We here addressed the effect of KRGW on HIF-1-mediated adaptation to hypoxia. In both Hep3B cancer and HEK293 immortalized normal cell lines, KRGW attenuated the expression of hypoxia-induced genes without apparent cytotoxicity. Mechanistically, KRGW did not affect the synthesis, degradation, and translocation of HIF-1α in hypoxia. Interestingly, KRGW was identified to repress the transcriptional activity of HIF-1α by interfering with the dimerization between HIF-1α and HIF-1β(ARNT). To identify HIF-inhibiting ingredient(s), we examined the effects of major ginsenosides on HIF-1 activity, but all ginsenosides tested failed to inactivate HIF-1. Based on these results, we propose that the HIF-1 inhibition underlies the anticancer effect of ginseng. It is also implied that KRGW could be an anticancer medicine to target hypoxic tumors.