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

Abstract

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.

• Authors: Yi-Chieh Lee, Tsan-Hwang Cheng, Jung-Shin Lee, Jiun-Hwan Chen, Yi-Chen Liao, Yao Fong, Cheng-Hsun Wu, Yuan-Wei Shih
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 347 Issue 1-2 Pg. 103-15 (Jan 2011) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 20963626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Actins (metabolism)
• Adenocarcinoma (enzymology, 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, pathology)
• DNA, Neoplasm (metabolism)
• Flavones (chemistry, 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, pathology)