Metastasis is one of the most important factors related to breast cancer therapeutic efficacy. Ursolic acid, a naturally occurring triterpenoid, has various anticancer activities. In this study, we first observed that ursolic acid exerted a dose- and time-dependent inhibitory effect on the migration and invasion of highly metastatic breast MDAMB231 cells at non-cytotoxic concentrations. This effect was associated with reduced activities of metalloproteinase-2 (MMP-2) and u-PA, which correlated with enhanced expression of tissue inhibitor of MMP-2 and plasminogen activator inhibitor-1, respectively. Ursolic acid suppressed the phosphorylation of Jun N-terminal kinase, Akt and mammalian target of rapamycin, but had no effect on the phosphorylation of ERK and p38. Ursolic acid also strongly reduced the levels of NFkB p65, c-Jun and c-Fos proteins in the nucleus of MDAMB231 cells. A time-dependent inhibition of the protein levels of Rho-like GTPases, growth factor receptor-bound protein 2, Ras and vascular endothelial growth factor in cytosol by ursolic acid treatment was also observed. In conclusion, we demonstrated that the anti-invasive effects of ursolic acid on MDAMB231 cells might be through the inhibition of Jun N-terminal kinase, Akt and mammalian target of rapamycin phosphorylation and a reduction of the level of NFkB protein in the nucleus, ultimately leading to downregulation of MMP-2 and u-PA expression. These results suggest that ursolic acid has potential as a chemopreventive agent for metastatic breast cancer.
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