ABSTRACT
Invasion and metastasis are among the main causes of death in patients with malignant tumors. Fisetin (3,3',4',7-tetrahydroxyflavone), a natural flavonoid found in the smoke tree (Cotinus coggygria), is known to have antimetastatic effects on prostate and lung cancers; however, the effect of fisetin on breast cancer metastasis is unknown. The aim of this study was to determine the anti-invasive activity of fisetin in human breast cancer cells. Matrix metalloproteinase (MMP)-9 is a major component facilitating the invasion of many cancer tumor cell types, and thus the inhibitory effect of fisetin on MMP-9 expression in 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated human breast cancer cells was investigated in this study. Fisetin significantly attenuated TPA-induced cell invasion in MCF-7 human breast cancer cells, and was found to inhibit the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways. This effect was furthermore associated with reduced NF-κB activation, suggesting that the anti-invasive effect of fisetin on MCF-7 cells may result from inhibited TPA activation of NF-κB and reduced TPA activation of PKCα/ROS/ERK1/2 and p38 MAPK signals, ultimately leading to the downregulation of MMP-9 expression. Our findings indicate the role of fisetin in MCF-7 cell invasion, and clarify the underlying molecular mechanisms of this role, suggesting fisetin as a potential chemopreventive agent for breast cancer metastasis.
Subject(s)
Breast Neoplasms/pathology , Flavonoids/pharmacology , MAP Kinase Signaling System/drug effects , Matrix Metalloproteinase 9/metabolism , Tetradecanoylphorbol Acetate/pharmacology , Cell Membrane/drug effects , Cell Membrane/metabolism , DNA/metabolism , Enzyme Activation/drug effects , Flavonols , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Neoplasm Invasiveness , Protein Kinase C-alpha/metabolism , Protein Transport/drug effects , Reactive Oxygen Species/metabolismABSTRACT
Cytokines produced by immune cells infiltrating pancreatic islets are important mediators of beta-cell destruction in insulin-dependent diabetes mellitus. Cytokines stimulate an inducible form of nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, leading to insulin insufficiency. In the present study, the effects of Artemisia capillaris extract (ACE) on cytokine-induced beta-cell damage were examined. Treatment of RINm5F (RIN) rat insulinoma cells with interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) induced cell damage. ACE completely protected IL-1beta and IFN-gamma-mediated cytotoxicity in a concentration-dependent manner. Incubation with ACE resulted in a significant reduction in IL-1beta and IFN-gamma-induced NO production, a finding that correlated well with reduced levels of the iNOS mRNA and protein. The molecular mechanism by which ACE inhibited iNOS gene expression appeared to involve the inhibition of NF-kappaB activation. The IL-1beta and IFN-gamma-stimulated RIN cells showed increases in NF-kappaB binding activity and p65 subunit levels in the nucleus, and IkappaBalpha degradation in cytosol compared to unstimulated cells. Furthermore, ACE restored the cytokine-induced inhibition of insulin release from isolated islets. These results suggest that ACE protects beta-cells by suppressing NF-kappaB activation.
