ABSTRACT
In breast cancer, the cytokine tumor necrosis factor-α (TNF-α) induces cell invasion, although the molecular basis of it has not been clearly elucidated. In this study, we investigated the role of daidzein in regulating TNF-α induced cell invasion and the underlying molecular mechanisms. Daidzein inhibited TNF-α induced cellular migration and invasion in estrogen receptor (ER) negative MCF10DCIS.com human breast cancer cells. TNF-α activated Hedgehog (Hh) signaling by enhancing Gli1 nuclear translocation and transcriptional activity, which resulted in increased invasiveness; these effects were blocked by daidzein and the Hh signaling inhibitors, cyclopamine and vismodegib. Moreover, these compounds suppressed TNF-α induced matrix metalloproteinase (MMP)-9 mRNA expression and activity. Taken together, mammary tumor cell invasiveness was stimulated by TNF-α induced activation of Hh signaling; these effects were abrogated by daidzein, which suppressed Gli1 activation, thereby inhibiting migration and invasion.
Subject(s)
Breast Neoplasms/physiopathology , Glycine max/chemistry , Hedgehogs/metabolism , Isoflavones/pharmacology , Oncogene Proteins/metabolism , Plant Extracts/pharmacology , Signal Transduction/drug effects , Trans-Activators/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cell Nucleolus/genetics , Cell Nucleolus/metabolism , Down-Regulation/drug effects , Female , Hedgehogs/genetics , Humans , Neoplasm Invasiveness/genetics , Oncogene Proteins/genetics , Trans-Activators/genetics , Tumor Necrosis Factor-alpha/genetics , Zinc Finger Protein GLI1ABSTRACT
This study employed the metabolomic approach to identify the key constituent exerting anti-inflammatory activity in murine macrophage RAW 264.7 cells. Among the six different fractions (SF1-SF6) of the strawberry 'Seolhyang', SF4 showed more significant inhibition on iNOS expression than SF3, and ellagic acid was determined as the most significant different component between SF4 and SF3 using orthogonal partial least-squares discriminant analysis. Ellagic acid (0.3 and 1.0 µM) and SF4 (100 µg/mL) were found to regulate the same inflammatory mediators, inhibitory κB (IκB) and mitogen-activated protein kinases (MAPKs), which led to the reduction of tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), and iNOS expressions. These results demonstrate that ellagic acid from strawberry 'Seolhyang' is the major component playing a crucial role in inflammation, suggesting the possible application of metabolomic analysis to determining the key ingredients having biological functions in the complicated food matrix.
