Stimulation of matrix metalloproteinase-9 expression in human fibrosarcoma cells by synthetic matrix metalloproteinase inhibitors.
Enhanced expression and activation of matrix metalloproteinase-2 (MMP-2) and MMP-9 have been associated with tumor progression, invasion, and metastasis. The use of synthetic MMP inhibitors to block the proteolytic activity of these enzymes recently emerged as a potential therapeutic tool to treat cancer. In this study, we report that GI129471, a synthetic broad-spectrum MMP inhibitor, efficiently reduced the in vitro invasiveness of HT1080 cells through type IV collagen, a major component of basement membranes. This reduced invasion was paralleled by a complete inhibition of pro-MMP-2 activation; however, GI129471 strongly increased the amount of secreted pro-MMP-9, which could be subsequently activated through a plasminogen-dependent mechanism. Quantitative RT-PCR and northern blot analysis revealed that GI129471 specifically increased the MMP-9 mRNA steady-state level. Moreover, transient transfection of HT1080 cells with beta-galactosidase reporter vectors containing different lengths of the 5'-flanking region of the MMP-9 gene revealed an upregulation of the transcriptional activity of the corresponding promoter. Well-known modulators of MMP-9 expression such as Il-1beta and TNF-alpha were not involved in this upregulation. These findings emphasize the complexity of the regulation of MMP expression and the requirement for a detailed characterization of the potential adverse side effects associated with the use of broad-spectrum MMPIs.
Maquoi
Erik
E
Laboratoire de Biologie des Tumeurs et du Développement, Université de Liège, Belgium.
Munaut
Carine
C
Colige
Alain
A
Lambert
Charles
C
Frankenne
Francis
F
Noël
Agnès
A
Grams
Frank
F
Krell
Hans-Willi
HW
Foidart
Jean-Michel
JM
D024141:Collagen Type IV / Q000494:pharmacology; D004789:Enzyme Activation; D005354:Fibrosarcoma / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D053583:Interleukin-1beta; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D024141:Collagen Type IV; D007375:Interleukin-1; D053583:Interleukin-1beta; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C052994:interleukin-1beta (163-171); C088672:GI 129471; D010649:Phenylalanine; D020780:Matrix Metalloproteinase 9