Fisetin Inhibits Migration and Invasion of Human Cervical Cancer Cells by Down-Regulating Urokinase Plasminogen Activator Expression through Suppressing the p38 MAPK-Dependent NF-κB Signaling Pathway

Abstract

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.

Fisetin inhibits the growth and migration in the A549 human lung cancer cell line via the ERK1/2 pathway

“…ERK1/2 may be activated by MEK1 (31). The results of the present study indicated that fisetin suppresses cell invasion by predominantly targeting the MAPK signaling pathway as the activation of ERK1/2 was markedly downregulated by fisetin at a high and low dose, which is consistent with previous results (32). Accordingly, it is suggested that fisetin suppresses NSCLCs cell growth via the ERK1/2 pathway.…”

Fisetin, a dietary flavonoid induces apoptosis via modulating the MAPK and PI3K/Akt signalling pathways in human osteosarcoma (U-2 OS) cells

“…Recent research have reported anti-proliferative (Chen et al, 2002;Haddad et al, 2006) and anti-metastasic effects (Chou et al, 2013) of fisetin, a polyphenolic flavonoid present in many fruits such as strawberries and cucumbers (Kim et al, 2012). Mechanisms through which fisetin exerts its action is yet to be elucidated completely, although it has been demonstrated to increase expressions of p53, down-regulate cyclin D1 and cyclin E levels (Chen et al, 2002;Lee et al, 2002;Lu et al, 2005b;Haddad et al, 2006).…”

Characteristic Features of Cytotoxic Activity of Flavonoids on Human Cervical Cancer Cells

“…It is a common malignancy of women remaining one of the leading causes of cancerrelated death worldwide (Hussain et al, 2012;Lo et al, 2012;Zeng et al, 2012a;Chen YJ et al, 2013a;Chou et al, 2013;Dayuthapani et al, 2013;Lo et al, 2013;Jin et al, 2014). According to the GLOBOCAN 2012 data, cervical cancer is the fourth most common cancer among women in terms of both incidence and mortality rates worldwide, with an estimated annual incidence of 528 000 new cases and 266 000 deaths in 2012 (Globocan2012).…”