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

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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.

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Abbreviations

MMPs:

Matrix metalloproteinases

ECM:

Extracellular matrix

PI3K/Akt:

Phosphoinositide 3-kinase/protein kinase B

NF-κB:

Nuclear factor kappa B

IκBα:

Inhibitor of kappaBα

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Acknowledgment

This work was supported by the grant from the Subsidized Project of the Chung Hwa University, Tainan, Taiwan (98-HT-08001).

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Authors and Affiliations

  1. Department of Biological Science and Technology and Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, No. 89, Wen-Hwa 1st Street, Jen-Te, Tainan, 717, Taiwan

    Yi-Chieh Lee, Tsan-Hwang Cheng & Yuan-Wei Shih

  2. Department of Optometry, Chung Hwa University of Medical Technology, No. 89, Wen-Hwa 1st Street, Jen-Te, Tainan, 717, Taiwan

    Jung-Shin Lee

  3. Department of Ophthalmology, Chi Mei Medical Center, No. 901, Jhong-Hua Road, Yong-Kang, Tainan, 710, Taiwan

    Jiun-Hwan Chen

  4. Department of Dermatology, Chi Mei Medical Center, No. 901, Jhong-Hua Road, Yong-Kang, Tainan, 710, Taiwan

    Yi-Chen Liao

  5. Department of Thoracic Surgery, Chi Mei Medical Center, No. 901, Jhong-Hua Road, Yong-Kang, Tainan, 710, Taiwan

    Yao Fong

  6. Department of Anatomy, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 402, Taiwan

    Cheng-Hsun Wu

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  1. Yi-Chieh Lee
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Correspondence to Cheng-Hsun Wu or Yuan-Wei Shih.

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Lee, YC., Cheng, TH., Lee, JS. et al. 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 347, 103–115 (2011). https://doi.org/10.1007/s11010-010-0618-z

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