URSOLIC ACID-INDUCED DOWN-REGULATION OF MMP-9 GENE IS MEDIATED THROUGH THE NUCLEAR TRANSLOCATION OF GLUCOCORTICOID RECEPTOR IN HT1080 HUMANFIBROSARCOMA CELLS

We have previously reported that ursolic acid, a pentacyclic triterpen e acid, inhibited the invasion of human fibrosarcoma cells by reducing : the of matrix metalloproteinase-9. Since the chemical structure of u rsolic acid is very similar to that of dexamethasone, a synthetic gluc ocorticoid, we investigated whether ursolic acid acts through the gluc ocorticoid receptor, The expression of matrix metalloproteinase-9 is t hought to be regulated similarly with matrix metalloproteinase-l and m atrix metalloproteinase-3 as containing common 2-O-tetradecanoylphorbo l-acetate responsible region, where AP-1 proteins can bind, Dexamethas one has been studied to repress the 2-O-tetradecanoylphorbol-acetate-i nduced expression of matrix metalloproteinase-l and matrix metalloprot einase-3 through a glucocorticoid receptor-mediated manner, In Norther n blot analysis, we found that ursolic acid reduced the expression of matrix metalloproteinase-l and matrix metalloproteinase-3 induced by 2 -O-tetradecanoylphorbol-acetate, Similarly, ursolic acid down-regulate d 2-O-tetradecanoylphorbol-acetate-induction of matrix metalloproteina se-9 gene in the same manner of dexamethasone. RU486, a potent glucoco rticoid receptor antagonist, was used for identifying that ursolic aci d-indnced down-regulation of matrix metalloproteinase-9 expression is mediated by its binding to glucocorticoid receptor, The effect of urso lic acid on the matrix metalloproteinase-9 expression was blocked by R U486, suggesting that ursolic acid acts via a glucocorticoid receptor in the regulation of matrix metalloproteinase-9, Western blot analysis and immunocytochemistry showed that ursolic acid increased glucocorti coid receptor fraction in the nucleus, although it decreased the synth esis of glucocorticoid receptor mRNA., In addition, ursolic acid did n ot decrease the expression of c-jun and DNA-binding activity of AP-1 t o its cognate sequences, Taken together, we suggest that ursolic acid may induce the repression of matrix metalloproteinase-9 by stimulating the nuclear translocation of glucocorticoid receptor, and the translo cated glucocorticoid receptor probably down-modulating the trans-activ ating function of AP-1 to 2-O-tetradecanoylphorbol-acetate responsible element of matrix metalloproteinase-9 promoter region.