Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1.

Abstract

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 factor-kappaB (NF-kappaB). The latter is activated by various carcinogens, inflammatory agents, and tumor promoters. Thus, agents that can suppress NF-kappaB 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 NF-kappaB is not understood. In the study described in the present report, we found that ursolic acid suppressed NF-kappaB activation induced by various carcinogens including tumor necrosis factor (TNF), phorbol ester, okadaic acid, H(2)O(2), and cigarette smoke. These effects were not cell type specific. Ursolic acid inhibited DNA binding of NF-kappaB consisting of p50 and p65. Ursolic acid inhibited IkappaBalpha degradation, IkappaBalpha phosphorylation, IkappaBalpha kinase activation, p65 phosphorylation, p65 nuclear translocation, and NF-kappaB-dependent reporter gene expression. Ursolic acid also inhibited NF-kappaB-dependent reporter gene expression activated by TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor, NF-kappaB-inducing kinase, IkappaBalpha kinase, and p65. The inhibition of NF-kappaB activation correlated with suppression of NF-kappaB-dependent cyclin D1, cyclooxygenase 2, and matrix metalloproteinase 9 expression. Thus, overall, our results indicate that ursolic acid inhibits IkappaBalpha kinase and p65 phosphorylation, leading to the suppression of NF-kappaB activation induced by various carcinogens. These actions of ursolic acid may mediate its antitumorigenic and chemosensitizing effects.