Involvement of the ERK signaling pathway in fisetin reduces invasion and migration in the human lung cancer cell line A549.
This study is the first to investigate the antimetastatic effect of fisetin in human lung adenocarcinoma A549 cells. Fisetin exhibited an inhibitory effect on the abilities of adhesion, migration, and invasion via inhibiting the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and downregulating the expressions of matrix metalloproteinase-2 (MMP-2) and urokinase-type plasminogen activator (u-PA) at both the protein and mRNA levels in A549 cells. Next, fisetin significantly decreased the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, treating A549 cells with fisetin also leads to a concentration-dependent inhibition on the binding abilities of NF-kappaB and activator protein-1 (AP-1). Furthermore, reduction of ERK1/2 phosphorylation by ERK small interfering RNA (ERK siRNA) potentiated the effect of fisetin, supporting the inhibition of ERK1/2 being beneficial to antimetastasis. Finally, the transient transfection of ERK siRNA significantly downregulated the expressions of MMP-2 and u-PA concomitantly with a marked inhibition of cell invasion and migration. Taken together, these results implied a critical role for ERK1/2 inhibition in fisetin-reduced invasion and migration of A549 cells.
Liao
Yi-Chen
YC
Department of Dermatology, Chi Mei Medical Center, Tainan, Taiwan, Republic of China.
Shih
Yuan-Wei
YW
Chao
Chang-Hung
CH
Lee
Xin-Yan
XY
Chiang
Tai-An
TA
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D044948:Flavonols; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; C017875:fisetin