Ursolic Acid Inhibits IL-1β or TNF-α-Induced C6 Glioma Invasion Through Suppressing the Association ZIP/p62 With PKC-ζ and Downregulating the MMP-9 Expression

Ursolic acid (UA), a constant constituent of Rosmarinus officinalis extracts, is a triterpenoid compound which has been shown to have antioxidant and anticarcinogenic properties. In the present study, we found that UA was able to reduce interleukin-1 beta (IL-1 beta) or tumor necrosis-alpha (TNF-alpha)-induced rat C6 glioma cell invasion, which was examined by a reconstituted basement membrane in a set of transwell chambers. However, the inhibitory effect of UA did not influence cell proliferation or cause cell cytotoxity. The results analyzed by zymography assay and Western blotting revealed that the activity and expression of matrix metalloproteinase-9 (MMP-9) was eliminated by UA in a dose-dependent manner. Because MMP-9 is the target gene of the transcription factor nuclear factor-kappaB (NF-kappa B), we further investigated the effect of UA on the activity of NF-kappa B. As expected, UA upregulated the levels of IkappaBalpha (I kappa B alpha) and attenuated the nuclear translocation of p65. Furthermore, UA suppressed the IL-1 beta or TNF-alpha-induced activation of protein kinase C-zeta (PKC-zeta). Our data showed UA potently inhibited the association of ZIP/p62 and PKC-zeta. Taken together, we demonstrated that UA could efficiently inhibit the interaction of ZIP/p62 and PKC-zeta. It also further suppressed the activation of NF-kappa B and downregulation of the MMP-9 protein, which in turn contributed to its inhibitory effects on IL-1 beta or TNF-alpha-induced C6 glioma cell invasion. These results all showcase the potential UA has in the chemoprevention and treatment of cancer metastasis and invasion. (C) 2008 Wiley-Liss, Inc.