Membrane-type 1 matrix metalloproteinase is regulated by Sp1 through the differential activation of AKT, JNK, and ERK pathways in human prostate tumor cells
Membrane-type 1 matrix metalloproteinase is regulated by Sp1 through the differential activation of AKT, JNK, and ERK pathways in human prostate tumor cells
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DOI：
10.1593/neo.07193
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发表时间：
2007-05-01
期刊：
影响因子：
4.8
通讯作者：
Bowden, G. Tim
中科院分区：
文献类型：
--
作者：
Sroka, Isis C.;Nagle, Raymond B.;Bowden, G. Tim
我们和其他研究人员之前已经表明，膜 1 型基质金属蛋白酶 (MT1-MMP) 在侵袭性前列腺癌细胞中过度表达。然而，这种表达的机制尚不清楚。在这里，我们发现 MT1-MMP 在非恶性原代前列腺细胞中最低表达，在 DU-145 细胞中中等表达，在侵袭性 PC-3 和 PC-3N 细胞中高表达。使用人 MT1-MMP 启动子报告质粒和迁移率变动分析，我们使用染色质免疫沉淀分析和沉默 RNA 表明 Sp1 调节 DU-145、PC-3 和 PC-3N 细胞以及 PC3-N 细胞中的 MT1-MMP 表达。信号通路研究表明，DU-145细胞组成型表达磷酸化细胞外应激调节激酶（ERK），而PC-3和PC-3N细胞组成型表达磷酸化AKT/PKB和c-Jun NH2末端激酶（JNK）。我们发现，当磷脂酰肌醇-3激酶和JNK受到抑制时，PC-3和PC-3N细胞中的MT1-MMP和Sp1水平降低，并且当MEK受到抑制时，DU-145细胞中MT1-MMP水平降低。用显性失活的 JNK 或 p85 瞬时转染 PC-3 和 PC-3N 细胞，以及用显性失活的 ERK 瞬时转染 DU-145 细胞，会降低 MT1-MMP 启动子活性。这些结果表明前列腺癌细胞系中 Sp1 介导的 MT1-MMP 转录调控存在差异信号控制。
We and other investigators have previously shown that membrane- type 1 matrix metalloproteinase ( MT1-MMP) is overexpressed in invasive prostate cancer cells. However, the mechanism for this expression is not known. Here, we show that MT1-MMP is minimally expressed in nonmalignant primary prostate cells, moderately expressed in DU- 145 cells, and highly expressed in invasive PC-3 and PC-3N cells. Using human MT1-MMP promoter reporter plasmids and mobility shift assays, we show that Sp1 regulates MT1-MMP expression in DU-145, PC-3, and PC-3N cells and in PC3-N cells using chromatin immunoprecipitation analysis and silencing RNA. Investigation of signaling pathway showed that DU- 145 cells express constitutively phosphorylated extracellular stress - regulated kinase ( ERK), whereas PC- 3 and PC-3N cells express constitutively phosphorylated AKT/PKB and c-Jun NH2 terminal kinase ( JNK). We show that MT1-MMP and Sp1 levels are decreased in PC- 3 and PC- 3N cells when phosphatidylinositol-3 kinase and JNK are inhibited, and that MT1-MMP levels are decreased in DU-145 cells when MEK is inhibited. Transient transfection of PC-3 and PC-3N cells with a dominant- negative JNK or p85, and of DU-145 cells with a dominant negative ERK, reduces MT1-MMP promoter activity. These results indicate differential signaling control of Sp1-mediated transcriptional regulation of MT1-MMP in prostate cancer cell lines.