Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3K/Akt and small GTPase signals in human gastric adenocarcinoma AGS cells

Mol Cell Biochem. 2011 Jan;347(1-2):103-15. doi: 10.1007/s11010-010-0618-z. Epub 2010 Oct 21.


Nobiletin, a compound isolated from citrus fruits, is a polymethoxylated flavone derivative shown to have anti-inflammatory, antitumor, and neuroprotective properties. This study has investigated that nobiletin exerted inhibitory effects on the cell adhesion, invasion, and migration abilities of a highly metastatic AGS cells under non-cytotoxic concentrations. Data also showed nobiletin could inhibit the activation of focal adhesion kinase (FAK) and phosphoinositide-3-kinase/Akt (PI3K/Akt) involved in the downregulation of the enzyme activities, protein expressions, messenger RNA levels of matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-2 (MMP-9). Also, our data revealed that nobiletin inhibited FAK/PI3K/Akt with concurrent reduction in the protein expressions of Ras, c-Raf, Rac-1, Cdc42, and RhoA by western blotting, whereas the protein level of RhoB increased progressively. Otherwise, nobiletin-treated AGS cells showed tremendously decreased in the phosphorylation and degradation of inhibitor of kappaBα (IκBα), the nuclear level of NF-κB, and the binding ability of NF-κB to NF-κB response element. Furthermore, nobiletin significantly decreased the levels of phospho-Akt and MMP-2/9 in Akt1-cDNA-transfected cells concomitantly with a marked reduction in cell invasion and migration. These results suggest that nobiletin can reduce invasion and migration of AGS cells, and such a characteristic may be of great value in the development of a potential cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / pathology
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Shape / drug effects
  • Cell Survival / drug effects
  • Citrus / chemistry*
  • Cytoskeleton / drug effects
  • Cytoskeleton / pathology
  • DNA, Neoplasm / metabolism
  • Flavones / chemistry
  • Flavones / pharmacology*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Humans
  • I-kappa B Proteins / metabolism
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Monomeric GTP-Binding Proteins / metabolism*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects*
  • Stomach Neoplasms / enzymology*
  • Stomach Neoplasms / pathology*


  • Actins
  • DNA, Neoplasm
  • Flavones
  • I-kappa B Proteins
  • Matrix Metalloproteinase Inhibitors
  • NF-kappa B
  • NFKBIA protein, human
  • NF-KappaB Inhibitor alpha
  • nobiletin
  • Phosphatidylinositol 3-Kinases
  • Focal Adhesion Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Monomeric GTP-Binding Proteins