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Inhibition of Activator Protein-1 Binding Activity and Phosphatidylinositol 3-Kinase Pathway by Nobiletin, a Polymethoxy Flavonoid, Results in Augmentation of Tissue Inhibitor of Metalloproteinases-1 Production and Suppression of Production of Matrix Metalloproteinases-1 and -9 in Human Fibrosarcoma HT-1080 Cells¹

Departments of Biochemistry [T. S., L. K., Y. M., M. H., A. I.] and Medicinal Plant Science [Y. M., Y. S.], Tokyo University of Pharmacy and Life Science, School of Pharmacy, Tokyo 192-0392; Bio-Oriented Technology Research Advancement Institution (BRAIN), Tokyo 105-0001 [M. H.]; and Department of Citriculture, Okitsu, National Institute of Fruit Tree Science, Shizuoka 424-0292 [M. Y.], Japan

Medicinal plants contain pharmacological substances including flavonoids, and their extracts have been therapeutically administered for cancer therapy in vitro and in vivo. We investigated the efficacy of a polymethoxy flavonoid, nobiletin, from Citrus depressa on tumor invasion in vitro. Nobiletin inhibited the tumor-invasive activity of human fibrosarcoma HT-1080 cells in the Matrigel model, whereas a similar inhibition was observed upon exogenously adding tissue inhibitors of metalloproteinases (TIMPs)-1 and -2. The gene expression and production of pro-matrix metalloproteinase 9 (proMMP-9)/progelatinase B and proMMP-1/interstitial procollagenase were specifically suppressed by nobiletin in 12-O-tetradecanoylphorbol 13-acetate-stimulated HT-1080 cells. In contrast, the gene expression and production of TIMP-1, but not TIMP-2, were enhanced by nobiletin. We also demonstrated that nobiletin suppressed the 12-O-tetradecanoylphorbol 13-acetate-induced binding activity of activator protein-1. Furthermore, a phosphatidylinositol 3-kinase inhibitor, LY-294002, was found to mimic the different actions of nobiletin on the production of proMMP-9 and TIMP-1. These results suggest that nobiletin inhibits tumor cell invasive activity not only by suppressing the expression of MMPs but also augmenting TIMP-1 production in tumor cells, and that the nobiletin-mediated inhibition of activator protein-1 binding activity is at least partly involved in the suppression of MMP expression. Furthermore, we suggest a possible mechanism by which nobiletin may interfere in the phosphatidylinositol 3-kinase pathway, which divergently regulates the production of MMP and TIMP-1.

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