Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappaB and c-Jun
Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappaB and c-Jun
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DOI：
10.1016/j.bcp.2004.09.019
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发表时间：
2005-01-15
影响因子：
5.8
通讯作者：
Lin, JK
中科院分区：
文献类型：
--
作者：
Huang, SC;Ho, CT;Lin, JK
鼠尾草酚是迷迭香提取物的一种稳定成分，是一种酚类二萜，具有抗氧化和抗癌作用。在我们的研究中，鼠尾草酚在体外抑制高转移性小鼠黑色素瘤B 16/F10细胞的侵袭。首先，通过软琼脂集落形成试验检测鼠尾草酚的抗转移潜力。第二，体外transwell实验发现鼠尾草酚呈剂量依赖性地抑制B16/F10细胞的迁移和侵袭。第三，通过酶谱分析观察到金属蛋白酶活性降低。结果表明，鼠尾草酚对MMP-9活性的抑制作用大于MMP-2。接下来，我们分析了细胞中MMP-9和MMP-2蛋白的量。数据表明MMP-9蛋白也以相同的方式被鼠尾草酚抑制。根据上述数据，逆转录聚合酶链反应（RT-PCR）分析结果显示MMP-9 mRNA水平降低。此外，鼠尾草酚还能显著抑制细胞外信号调节激酶（ERK）1/2、AKT、p38、JNK的酪氨酸磷酸化，抑制转录因子NFK-B和c-Jun的活化，从而抑制B16/F10小鼠黑色素瘤细胞的侵袭能力。p38和JNK信号传导途径以及抑制NF-κ B和AP-1结合活性。总之，这些结果表明鼠尾草酚靶向癌细胞中的NIMP介导的细胞事件，并为其抗癌活性提供了新的机制。(C)2004年爱思唯尔公司All rights reserved.
Carnosol, a constant constituent of Rosmarinus officinalis extracts, is a phenolic diterpene shown to have antioxidant and anticarcinogen properties. In our studies, carnosol inhibited the invasion of highly metastatic mouse melanoma B 16/F10 cells in vitro. First, the antimetastatic potentials of carnosol were examined by soft agar colony formation assay. Second, carnosol dose-dependently inhibited B16/F10 cell migration and invasion by in vitro transwell assay. Third, the decreasing activity of metalloproteinase was observed by zymographic assay. The result revealed that the treatment of carnosol could diminish the activity of MMP-9 more than MMP-2. Next, we analyzed the amounts of MMP-9 and MMP-2 proteins in the cells. The data indicated MMP-9 protein was also suppressed by carnosol in the same manner. In accordance with the above data, the results of reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed a reduced level of MMP-9 mRNA. Furthermore, carnosol significantly inhibited the tyrosine phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, AKT, p38, JNK and inhibition of activation of transcription factors NFK-B and c-Jun. These results lead us to conclude that carnosol could restrict the invasive ability of B16/F10 mouse melanoma cells by reducing MMP-9 expression and activity through suppressing (ERK) 1/2, AKT, p38, and JNK signaling pathway and inhibition of NF-KB and AP-1 binding activity. Taken together, these results indicate that carnosol targets NIMP-mediated cellular events in cancer cells and provides a new mechanism for its anticancer activity.(C) 2004 Elsevier Inc. All rights reserved.