Red ginseng deregulates hypoxia-induced genes by dissociating the HIF-1 dimer

Water extract of Korean red ginseng (KRGW) contains numerous bioactive ginsenosides and is very popular 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 hypoxia-inducible factor-1 (HIF-1) plays critical roles in tumor promotion under hypoxia and that it is a compelling target for cancer therapy. In this paper we investigated 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-1 in hypoxia. Interestingly, KRGW was found to repress the transcriptional activity of HIF-1 by interfering with the dimerization between HIF-1 alpha and aryl hydrocarbon receptor nuclear translocator. To identify the 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 HIF-1 inhibition underlies the anticancer effect of ginseng. It is also proposed that KRGW could be an anticancer drug targeting hypoxic tumors.