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

被引:107
作者
Lee, Yi-Chieh [1 ,2 ]
Cheng, Tsan-Hwang [1 ,2 ]
Lee, Jung-Shin [3 ]
Chen, Jiun-Hwan [4 ]
Liao, Yi-Chen [5 ]
Fong, Yao [6 ]
Wu, Cheng-Hsun [7 ]
Shih, Yuan-Wei [1 ,2 ]
机构
[1] Chung Hwa Univ Med Technol, Dept Biol Sci & Technol, Tainan 717, Taiwan
[2] Chung Hwa Univ Med Technol, Grad Inst Biomed Sci, Tainan 717, Taiwan
[3] Chung Hwa Univ Med Technol, Dept Optometry, Tainan 717, Taiwan
[4] Chi Mei Med Ctr, Dept Ophthalmol, Tainan 710, Taiwan
[5] Chi Mei Med Ctr, Dept Dermatol, Tainan 710, Taiwan
[6] Chi Mei Med Ctr, Dept Thorac Surg, Tainan 710, Taiwan
[7] China Med Univ, Dept Anat, Taichung 402, Taiwan
关键词
Nobiletin; Invasion; Migration; FAK; PI3K/Akt; MMP-2; MMP-9; FOCAL ADHESION KINASE; NF-KAPPA-B; CANCER-CELLS; DOWN-REGULATION; EXPRESSION; PATHWAY; RAS; METASTASIS; GROWTH; FAK;
D O I
10.1007/s11010-010-0618-z
中图分类号
Q2 [细胞生物学];
学科分类号
071013 [干细胞生物学];
摘要
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 kappaB alpha (I kappa B alpha), the nuclear level of NF-kappa B, and the binding ability of NF-kappa B to NF-kappa B 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.
引用
收藏
页码:103 / 115
页数:13
相关论文
共 39 条
[1]
DIRECT EVIDENCE LINKING EXPRESSION OF MATRIX METALLOPROTEINASE-9 (92-KDA GELATINASE/COLLAGENASE) TO THE METASTATIC PHENOTYPE IN TRANSFORMED RAT EMBRYO CELLS [J].
BERNHARD, EJ ;
GRUBER, SB ;
MUSCHEL, RJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (10) :4293-4297
[2]
Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression [J].
Canel, M. ;
Secades, P. ;
Garzon-Arango, M. ;
Allonca, E. ;
Suarez, C. ;
Serrels, A. ;
Frame, M. C. ;
Brunton, V. ;
Chiara, M-D .
BRITISH JOURNAL OF CANCER, 2008, 98 (07) :1274-1284
[3]
Mulberry Leaf Extract Inhibits Vascular Smooth Muscle Cell Migration Involving a Block of Small GTPase and Akt/NF-κB Signals [J].
Chan, Kuei-Chuan ;
Ho, Hsieh-Hsun ;
Huang, Chien-Ning ;
Lin, Ming-Cheng ;
Chen, Hsiang-Mei ;
Wang, Chau-Jong .
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 2009, 57 (19) :9147-9153
[4]
Two new polymethoxylated flavones, a class of compounds with potential anticancer activity, isolated from cold pressed Dancy tangerine peel oil solids [J].
Chen, J ;
Montanari, AM ;
Widmer, WW .
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 1997, 45 (02) :364-368
[5]
Group IB secretory phospholipase A2 promotes matrix metalloproteinase-2-mediated cell migration via the phosphatidylinositol 3-kinase and Akt pathway [J].
Choi, YA ;
Lim, HK ;
Kim, JR ;
Lee, CH ;
Kim, YJ ;
Kang, SS ;
Baek, SH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (35) :36579-36585
[6]
Agents targeting Ras signaling pathway [J].
Dancey, JE .
CURRENT PHARMACEUTICAL DESIGN, 2002, 8 (25) :2259-2267
[7]
Hauck CR, 2001, CANCER RES, V61, P7079
[8]
A RAPID MICROSCALE PROCEDURE FOR THE SIMULTANEOUS PREPARATION OF CYTOPLASMIC RNA, NUCLEAR-DNA BINDING-PROTEINS AND ENZYMATICALLY ACTIVE LUCIFERASE EXTRACTS [J].
HOPPESEYLER, F ;
BUTZ, K ;
RITTMULLER, C ;
DOEBERITZ, MV .
NUCLEIC ACIDS RESEARCH, 1991, 19 (18) :5080-5080
[9]
CCL5 increases lung cancer migration via PI3K Akt and NF-κB pathways [J].
Huang, Chun-Yin ;
Fong, Yi-Chin ;
Lee, Chun-Yi ;
Chen, Meng-Yi ;
Tsai, Hsiao-Chi ;
Hsu, Horny-Chaung ;
Tang, Chih-Hsin .
BIOCHEMICAL PHARMACOLOGY, 2009, 77 (05) :794-803
[10]
Rac1 promotes TGF-β-stimulated mesangial cell type I collagen expression through a PI3K/Akt-dependent mechanism [J].
Hubchak, Susan C. ;
Sparks, Erin E. ;
Hayashida, Tomoko ;
Schnaper, H. William .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2009, 297 (05) :F1316-F1323