Ursolic Acid Inhibits Nuclear Factor- B Activation Induced by Carcinogenic Agents through Suppression of I B Kinase and p65 Phosphorylation: Correlation with Down-Regulation of Cyclooxygenase 2, Matrix Metalloproteinase 9, and Cyclin D1

The process of tumorigenesis requires cellular transformation, hyperproliferation, invasion, angiogenesis, and metastasis. Several genes that mediate these processes are regulated by the transcription factor nuclear factorB (NFB). The latter is activated by various carcinogens, inflammatory agents, and tumor promoters. Thus, agents that can suppress NFB activation have the potential to suppress carcinogenesis. Ursolic acid, a pentacyclic triterpene acid, has been shown to suppress the expression of several genes associated with tumorigenesis, but whether ursolic acid mediates its effects through suppression of NFB is not understood. In the study described in the present report, we found that ursolic acid suppressed NFB activation induced by various carcinogens including tumor necrosis factor (TNF), phorbol ester, okadaic acid, H2O2, and cigarette smoke. These effects were not cell type specific. Ursolic acid inhibited DNA binding of NFB consisting of p50 and p65. Ursolic acid inhibited I B degradation, I B phosphorylation, I B kinase activation, p65 phosphorylation, p65 nuclear translocation, and NFB-dependent reporter gene expression. Ursolic acid also inhibited NFB-dependent reporter gene expression activated by TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor, NFB-inducing kinase, I B kinase, and p65. The inhibition of NFB activation correlated with suppression of NFB-dependent cyclin D1, cyclooxygenase 2, and matrix metalloproteinase 9 expression. Thus, overall, our results indicate that ursolic acid inhibits I B kinase and p65 phosphorylation, leading to the suppression of NFB activation induced by various carcinogens. These actions of ursolic acid may mediate its antitumorigenic and chemosensitizing effects.