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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.

Chou RH, Hsieh SC, Yu YL, Huang MH, Huang YC, Hsieh YH - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.

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.

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The proposed fisetin model in inhibiting the migration and invasion of cervical cancer cells.Fisetin inhibits the phosphorylation of p38 MAPK and impairs translocation of NF-κB to the nucleus. The decreased NF-κB in the nucleus reduces its binding on the promoter of the uPA gene, and results in repressing the expression and activity of uPA, thereby disrupting the migratory and invasive ability of cervical cancer SiHa cells.
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pone-0071983-g007: The proposed fisetin model in inhibiting the migration and invasion of cervical cancer cells.Fisetin inhibits the phosphorylation of p38 MAPK and impairs translocation of NF-κB to the nucleus. The decreased NF-κB in the nucleus reduces its binding on the promoter of the uPA gene, and results in repressing the expression and activity of uPA, thereby disrupting the migratory and invasive ability of cervical cancer SiHa cells.

Mentions: We uncovered the anti-metastatic potential of fisetin in cervical cancer cells and elucidated its molecular mechanism, that is fisetin inhibits the activation of p38 MAPK, impairs translocation of NF-κB to the nucleus, and then decreases its binding amounts on the promoter of uPA gene, and results in repressing the expression and activity of uPA, leading to disrupting the invasiveness and motility of cervical cancer cells (Figure 7).


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.

Chou RH, Hsieh SC, Yu YL, Huang MH, Huang YC, Hsieh YH - PLoS ONE (2013)

The proposed fisetin model in inhibiting the migration and invasion of cervical cancer cells.Fisetin inhibits the phosphorylation of p38 MAPK and impairs translocation of NF-κB to the nucleus. The decreased NF-κB in the nucleus reduces its binding on the promoter of the uPA gene, and results in repressing the expression and activity of uPA, thereby disrupting the migratory and invasive ability of cervical cancer SiHa cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3733924&req=5

pone-0071983-g007: The proposed fisetin model in inhibiting the migration and invasion of cervical cancer cells.Fisetin inhibits the phosphorylation of p38 MAPK and impairs translocation of NF-κB to the nucleus. The decreased NF-κB in the nucleus reduces its binding on the promoter of the uPA gene, and results in repressing the expression and activity of uPA, thereby disrupting the migratory and invasive ability of cervical cancer SiHa cells.
Mentions: We uncovered the anti-metastatic potential of fisetin in cervical cancer cells and elucidated its molecular mechanism, that is fisetin inhibits the activation of p38 MAPK, impairs translocation of NF-κB to the nucleus, and then decreases its binding amounts on the promoter of uPA gene, and results in repressing the expression and activity of uPA, leading to disrupting the invasiveness and motility of cervical cancer cells (Figure 7).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.

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.

Show MeSH
Related in: MedlinePlus