The p75(NTR) metastasis suppressor inhibits urokinase plasminogen activator, matrix metalloproteinase-2 and matrix metalloproteinase-9 in PC-3 prostate cancer cells.
The p75 neurotrophin receptor (p75(NTR)) has been characterized as a metastasis and tumor suppressor in prostate cancer. In order to investigate the mechanism(s) by which the p75(NTR) functions as a metastasis suppressor in prostate cancer cells, we characterized the ectopic expression of p75(NTR) on the urokinase plasminogen activator (uPA) and the type IV collagen matrix metalloproteinases (MMP-2 and MMP-9) in PC-3 human prostate cancer cells. Rank-order expression of p75(NTR) greatly reduced protein levels and enzymatic activities of uPA, MMP-2, and MMP-9 as shown by immunoblot and zymography analyses. Conversely, expression of the MMP-9 antagonist, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) exhibited an increase in protein levels with an increase in p75(NTR) levels, whereas TIMP-2 was not detected. Transient transfection with an inducible dominant negative antagonist Deltap75(NTR) rescued uPA, MMP-2, and MMP-9 protein levels and protease activities, and conversely suppressed TIMP-1 levels. Since p75(NTR) signal transduction occurs via the NFkappaB and JNK pathways, antagonism of signaling intermediates in these pathways, using dominant negative IKKbeta or dominant negative MKK-4, respectively, was shown to further decrease expression of uPA, MMP-2, and MMP-9 protein and enzymatic activity levels, and conversely up-regulate levels of TIMP-1. These results indicate that expression of uPA, MMP-2, MMP-9, and TIMP-1 are directly regulated by expression of p75(NTR) and its downstream signal transduction cascade. These results suggest that the metastasis suppressor activity of p75(NTR) is mediated, in part, by down-regulation of specific proteases (uPA, type IV collagenases) implicated in cell migration and metastasis.
Nalbandian
Angèle
A
Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Medical Dental Building, Washington, DC 20057-1436, USA.
Djakiew
Daniel
D
D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020782:Matrix Metalloproteinases; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D019715:Tissue Inhibitor of Metalloproteinase-1; D025521:Tumor Suppressor Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9