Acacetin Inhibits TPA-Induced MMP-2 and u-PA Expressions of Human Lung Cancer Cells Through Inactivating JNK Signaling Pathway and Reducing Binding Activities of NF-κB and AP-1
Acacetin Inhibits TPA-Induced MMP-2 and u-PA Expressions of Human Lung Cancer Cells Through Inactivating JNK Signaling Pathway and Reducing Binding Activities of NF-κB and AP-1
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DOI：
10.1111/j.1750-3841.2009.01438.x
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发表时间：
2010-01-01
影响因子：
3.9
通讯作者：
Shih, Yuan-Wei
中科院分区：
文献类型：
--
作者：
Fong, Yaou;Shen, Kun-Hung;Shih, Yuan-Wei
金合欢素（5，7-二羟基-4 '-甲氧基黄酮）是一种黄酮类化合物，具有抗氧化和抗衰老作用。研究了金合欢素对12-O-十四酰佛波醇-13-乙酸酯（TPA）诱导的人肺癌A549细胞MMPs和u-PA表达的影响。首先，通过细胞-基质粘附实验和Boyden小室实验证明金合欢素能抑制TPA诱导的粘附、侵袭和迁移能力。金合欢素可抑制c-Jun N-末端激酶1和2（JNK 1/2）的磷酸化，从而下调TPA诱导的基质金属蛋白酶-2（MMP-2）和尿激酶型纤溶酶原激活物（u-PA）的蛋白表达和转录。此外，金合欢素还能显著抑制TPA刺激的核因子κ B（NF-κ B）、c-Fos和c-Jun的核水平，并进一步观察到金合欢素对NF-κ B与激活蛋白-1（AP-1）结合能力的抑制作用，其抑制作用呈剂量依赖性。此外，INK特异性抑制剂（SP 600125）处理A549细胞，可以沿着抑制TPA诱导的MMP-2和u-PA表达，并抑制细胞侵袭和迁移。综上所述，这些结果表明，刺槐素对TPA诱导的A549细胞的抗转移作用可能是通过抑制INK磷酸化并降低NF-κ B和AP-1结合活性来减少MMP-2和u-PA表达。
Acacetin (5,7-dihydroxy-4'-methoxyflavone), a flavonoid compound, has antiperoxidative and antiinflammatory effects. The effect of acacetin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMPs and u-PA expressions in human lung cancer A549 cells was investigated. First, the result demonstrated acacetin could inhibit TPA-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and Boyden chamber assay. Data also showed acacetin could inhibit phosphorylation of c-Jun N-terminal-kinase 1 and 2 (JNK1/2) involved in the down-regulating protein expressions and transcriptions of matrix metalloproteinase-2 (MMP-2) and urokinase-type plasminogen activator (u-PA) induced by TPA. Next, acacetin also strongly inhibited TPA-stimulated the nuclear levels of nuclear factor kappa B (NF-kappa B), c-Fos, and c-Jun. Also, a dose-dependent inhibition on the binding abilities of NF-kappa B and activator protein-1 (AP-1) by acacetin treatment was further observed. Further, the treatment of specific inhibitor for INK (SP600125) to A549 cells could inhibit TPA-induced MMP-2 and u-PA expressions along with an inhibition on cell invasion and migration. Taken together, these results suggest the antimetastatic effects of acacetin on the TPA-induced A549 cells might be by reducing MMP-2 and u-PA expressions through inhibiting phosphorylation of INK and reducing NF-kappa B and AP-1 binding activities.