Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
PLoS One. 2013 Aug 5;8(8):e71983. doi: 10.1371/journal.pone.0071983. Print 2013.
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.
漆黄素（3,3',4',7-四羟基黄酮）是一种天然存在的类黄酮，据报道它能抑制几种癌症类型的增殖并诱导细胞凋亡。然而，其对宫颈癌转移潜能的抑制作用尚不清楚。在本研究中，我们发现漆黄素能抑制宫颈癌细胞的侵袭和迁移。漆黄素能以剂量依赖性方式显著抑制尿激酶纤溶酶原激活物（uPA）的表达和活性。我们还表明，漆黄素能降低 p38 MAPK 的磷酸化，但不影响 ERK1/2、JNK1/2 或 AKT 的磷酸化。添加 p38 MAPK 抑制剂 SB203580 能进一步增强漆黄素对 uPA 的表达和活性以及宫颈癌细胞侵袭和迁移的抑制作用。漆黄素能抑制 TPA（十四烷酰佛波醇-13-醋酸酯）诱导的 p38 MAPK 和 uPA 的激活，并抑制 TPA 增强的迁移和侵袭能力。此外，漆黄素能显著抑制 uPA 基因的启动子活性，破坏 NF-κB 的核转位及其与 uPA 基因启动子的结合量，且 SB203580 能进一步增强这些抑制作用。本研究为漆黄素通过阻断 p38 MAPK 依赖性 NF-κB 信号通路抑制 uPA 从而抑制宫颈癌细胞侵袭和迁移的分子机制提供了有力证据，并为通过抑制迁移和侵袭将漆黄素作为治疗宫颈癌的策略提供了新的见解。
