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 cells.
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.
Sato
Takashi
T
Department of Biochemistry, Tokyo University of Pharmacy and Life Science, School of Pharmacy, Hachioji, Tokyo 192-0392, Japan. satotak@ps.toyaku.ac.jp
Koike
Leona
L
Miyata
Yoshiki
Y
Hirata
Michiko
M
Mimaki
Yoshihiro
Y
Sashida
Yutaka
Y
Yano
Masamichi
M
Ito
Akira
A
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005354:Fibrosarcoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D047309:Flavones; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D047309:Flavones; D005419:Flavonoids; D061965:Matrix Metalloproteinase Inhibitors; D009025:Morpholines; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D018808:Transcription Factor AP-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C008661:nobiletin; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1