Fisetin (3,3',4',7-tetrahydroxyflavone), a naturally occurring
flavonoid, has been reported to inhibit proliferation and induce apoptosis in several
cancer types. However, its effect on the anti-metastatic potential of
cervical cancer cells remains unclear. In the present study, we found that
fisetin inhibits the invasion and migration of
cervical cancer cells. The expression and activity of
urokinase plasminogen activator (uPA) was significantly suppressed by
fisetin in a dose-dependent manner. We also demonstrated that
fisetin reduces the phosphorylation of
p38 MAPK, but not that of ERK1/2, JNK1/2, or AKT. Addition of a
p38 MAPK inhibitor,
SB203580, further enhanced the inhibitory effect of
fisetin on the expression and activity of uPA and the invasion and motility in
cervical cancer cells.
Fisetin suppressed the TPA (tetradecanoylphorbol-13-acetate)-induced activation of
p38 MAPK and uPA, and inhibited the TPA-enhanced migratory and invasive abilities. Furthermore, the promoter activity of the uPA gene was dramatically repressed by
fisetin, which disrupted the nuclear translocation of NF-κB and its binding amount on the promoter of the uPA gene, and these suppressive effects could be further enhanced by
SB203580. This study provides strong evidence for the molecular mechanism of
fisetin in inhibiting the aggressive phenotypes by repression of uPA via interruption of
p38 MAPK-dependent NF-κB signaling pathway in
cervical cancer cells and thus contributes insight to the potential of using
fisetin as a therapeutic strategy against
cervical cancer by inhibiting migration and invasion.