Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
Int J Biochem Cell Biol. 2012 Dec;44(12):2212-22. doi: 10.1016/j.biocel.2012.08.021. Epub 2012 Sep 3.
This study explores the CIL-102 suppression mechanism on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression in human leukemia K562 cells. CIL-102 attenuated K562 cell invasion with decreased MMP-2/MMP-9 protein expression and mRNA levels. Moreover, CIL-102 reduced luciferase activity of MMP-2/MMP-9 promoter constructs and MMP-2/MMP-9 mRNA stability. CIL-102 treatment induced JNK and p38 MAPK activation but reduced the phospho-ERK level. Transfection of constitutively active MEK1 restored MMP-2 and MMP-9 promoter activity in CIL-102-treated cells, while suppression of p38 MAPK/JNK activation abolished CIL-102-induced MMP-2/MMP-9 mRNA decay. CIL-102-induced p38 MAPK/JNK activation led to protein phosphatase 2A-mediated tristetraprolin (TTP) down-regulation. The reduction in TTP-KH-type splicing regulatory protein (KSRP) complexes formation promoted KSRP-mediated MMP-2/MMP-9 mRNA decay in CIL-102-treated K562 cells. Moreover, CIL-102 reduced invasion and MMP-2/MMP-9 expression in breast and liver cancer cells. Taken together, our data indicate that CIL-102 induces MMP-2/MMP-2 down-regulation via simultaneous suppression of genetic transcription and mRNA stability, and suggest a potential utility for CIL-102 in reducing MMP-2/MMP-9-mediated cancer progression.
本研究探讨了 CIL-102 对人白血病 K562 细胞基质金属蛋白酶-2（MMP-2）和 MMP-9 表达的抑制机制。CIL-102 通过降低 MMP-2/MMP-9 蛋白表达和 mRNA 水平来减弱 K562 细胞的侵袭能力。此外，CIL-102 降低了 MMP-2/MMP-9 启动子构建体和 MMP-2/MMP-9 mRNA 稳定性的荧光素酶活性。CIL-102 处理诱导 JNK 和 p38 MAPK 的激活，但降低了磷酸化 ERK 水平。转染组成型激活的 MEK1 恢复了 CIL-102 处理细胞中 MMP-2 和 MMP-9 启动子的活性，而抑制 p38 MAPK/JNK 的激活则消除了 CIL-102 诱导的 MMP-2/MMP-9 mRNA 降解。CIL-102 诱导的 p38 MAPK/JNK 激活导致蛋白磷酸酶 2A 介导的 tristetraprolin（TTP）下调。TTP-KH 型剪接调节蛋白（KSRP）复合物形成的减少促进了 CIL-102 处理的 K562 细胞中 KSRP 介导的 MMP-2/MMP-9 mRNA 降解。此外，CIL-102 降低了乳腺癌和肝癌细胞的侵袭和 MMP-2/MMP-9 表达。综上所述，我们的数据表明，CIL-102 通过同时抑制基因转录和 mRNA 稳定性来诱导 MMP-2/MMP-9 的下调，并提示 CIL-102 在减少 MMP-2/MMP-9 介导的癌症进展方面具有潜在的应用价值。
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