4′,6-Dihydroxy-4-methoxyisoaurone inhibits the HIF-1α pathway through inhibition of Akt/mTOR/p70S6K/4E-BP1 phosphorylation

4′,6-dihydroxy-4-methoxyisoaurone (isoa) is an isoaurone compound isolated from trichosanthes kirilowii seeds,which was identified as an inhibitor of tumor growth. however,the mechanism by which isoa inhibits hypoxia-inducible factor-1 (hif-1)-mediated tumor growth is not fully understood. we here demonstrated the effect of isoa on hif-1 activation. isoa showed a potent inhibitory activity against hif-1 activation induced by hypoxia in various human cancer cell lines. this compound markedly decreased the hypoxia-induced accumulation of hif-1α protein dose-dependently,whereas it did not affect the expressions of hif-1β and topoisomerase-i (topo-i). further analysis revealed that the suppression of hif-1α accumulation by isoa was closely correlated with strong dephosphorylation of akt,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-1α expression at the translational level. furthermore,isoa prevented hypoxia-induced expression of hif-1 target genes and suppresses the invasiveness of tumor cells. taken together,our results suggested that isoa is an effective inhibitor of hif-1 through targeting akt/mtor/p70s6k/4e-bp1 pathway,thereby,providing new perspectives into the mechanism of its anticancer activity. © the japanese pharmacological society.