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Carcinogenesis |
B Activation Induced by Carcinogenic Agents through Suppression of IB
Kinase and p65 Phosphorylation
Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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-
B (NF-B). The latter is activated by various carcinogens, inflammatory agents, and tumor promoters. Thus, agents that can suppress NF-B 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-B is not understood. In the study described in the present report, we found that ursolic acid suppressed NF-B 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 NF-B consisting of p50 and p65. Ursolic acid inhibited IB
degradation, IB phosphorylation, IB kinase activation, p65 phosphorylation, p65 nuclear translocation, and NF-B-dependent reporter gene expression. Ursolic acid also inhibited NF-B-dependent reporter gene expression activated by TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor, NF-B-inducing kinase, IB kinase, and p65. The inhibition of NF-B activation correlated with suppression of NF-B-dependent cyclin D1, cyclooxygenase 2, and matrix metalloproteinase 9 expression. Thus, overall, our results indicate that ursolic acid inhibits IB kinase and p65 phosphorylation, leading to the suppression of NF-B activation induced by various carcinogens. These actions of ursolic acid may mediate its antitumorigenic and chemosensitizing effects.
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