Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells

Abstract

We have previously reported that ursolic acid, a pentacyclic triterpene acid, inhibited the invasion of HT1080 human ®brosarcoma cells by reducing the expression of matrix metalloproteinase-9. Since the chemical structure of ursolic acid is very similar to that of dexamethasone, a synthetic glucocorticoid, we investigated whether ursolic acid acts through the glucocorticoid receptor. The expression of matrix metalloproteinase-9 is thought to be regulated similarly with matrix metalloproteinase-1 and matrix metalloproteinase-3 as containing common 2-O-tetradecanoylphorbol-acetate responsible region, where AP-1 proteins can bind. Dexamethasone has been studied to repress the 2-O-tetradecanoylphorbolacetate-induced expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 through a glucocorticoid receptor-mediated manner. In Northern blot analysis, we found that ursolic acid reduced the expression of matrix metalloproteinase-1 and matrix metalloproteinase-3 induced by 2-O-tetradecanoylphorbol-acetate. Similarly, ursolic acid down-regulated 2-O-tetradecanoylphorbolacetate-induction of matrix metalloproteinase-9 gene in the same manner of dexamethasone. RU486, a potent glucocorticoid receptor antagonist, was used for identifying that ursolic acid-induced down-regulation of matrix metalloproteinase-9 expression is mediated by its binding to glucocorticoid receptor. The e ect of ursolic acid on the matrix metalloproteinase-9 expression was blocked by RU486, 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 glucocorticoid receptor fraction in the nucleus, although it decreased the synthesis of glucocorticoid receptor mRNA. In addition, ursolic acid did not decrease the expression of c-jun and DNAbinding activity of AP-1 to 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 translocated glucocorticoid receptor probably downmodulating the trans-activating function of AP-1 to 2-Otetradecanoylphorbol-acetate responsible element of matrix metalloproteinase-9 promoter region.

Ursolic Acid, a Pentacyclin Triterpene, Potentiates TRAIL-induced Apoptosis through p53-independent Up-regulation of Death Receptors

“…UA induces apoptosis through multiple pathways, such as inhibiting DNA replication (7,10); inducing Ca 2ϩ release (8); activating caspases (9,11); activating JNK (12); down-regulating antiapoptotic genes (13,14); inhibiting COX2 and iNOS (15,16); suppressing MMP-9 (17); and inhibiting protein tyrosine kinase (10), STAT3 (18), and NF-B activities (13). In animal studies, UA has been shown to be chemopreventive (19 -21), to suppress tumor invasion (17), and to inhibit experimental metastasis of esophageal carcinoma (22). Whether UA can modulate the effect of apoptosisinducing cytokines that are currently in clinical trial is not known.…”

Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling

“…In breast cancer patients, TFAP2A is highly associated with MMP9 expression (Pellikainen et al, 2004). NRC3C1 is a nuclear receptor that can inhibit expression of MMP9 (Cha et al, 1988). In conjunction with elevated levels of HMGA1 and TFAP2, reduced expression of this gene may lead to increased MMP9 activity.…”

A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumors

“…Although the concrete mechanisms of its anticancer effects are poorly understood, several studies have found that UA can inhibit proliferation and induce apoptosis of many tumor cell lines. 2 UA-induced apoptosis occurs through multiple pathways such as the inhibition of DNA replication, 3 induction of Ca 2+ release, 4 activation of caspases 5,6 and c-Jun N-terminal kinase, 7,8 phosphorylation of glycogen synthase kinase 3-β, downregulation of antiapoptotic genes, 9 inhibition of cyclooxygenase-2 and inducible nitric oxide synthase, 10,11 suppression of matrixmetallopeptidase-9, 12 and the inhibition of protein tyrosine kinase, 13 phosphatidylinositol-3-kinase, 14 single transducer and activator of transcription 3, 15 adenosine 5′-monophosphate-activated protein kinase, 16 and nuclear factor κ-light-chain-enhancer of activated B cells 17 pathways. Furthermore, UA can inhibit the differentiation, angiogenesis, invasion, and metastasis of tumor cells as well as interfere with numerous enzymes such as those directly involved with DNA synthesis and repair.…”