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.
Sroka
Isis C
IC
Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
Nagle
Raymond B
RB
Bowden
G Tim
GT
D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D016329:Sp1 Transcription Factor / Q000502:physiology*
D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053511:Matrix Metalloproteinase 14