Membrane-type 1 matrix metalloproteinase is regulated by Sp1 through the differential activation of AKT, JNK, and ERK pathways in human prostate tumor cells

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.