Opposing function of the proprotein convertases furin and PACE4 on breast cancer cells' malignant phenotypes: role of tissue inhibitors of metalloproteinase-1.
Proteolytic cleavage of various cancer-related substrates by the proprotein convertases (PC) was reported to be important in the processes of neoplasia. These enzymes are inhibited by their naturally occurring inhibitors, the prosegments (ppPC), and by the engineered general PC inhibitor, the serpin variant alpha1-PDX. In the present study, we sought to compare the effect of these PC inhibitors on malignant phenotypes of breast cancer cells. Overexpression in a stable manner of alpha1-PDX and the prosegment ppPACE4 in MDA-MB-231 breast cancer cells resulted in increased matrix metalloproteinase (MMP)-9 (but not MMP-2) activity and a reduced secretion of tissue inhibitor of metalloproteinase 1 (TIMP-1). This was associated with significant enhancement in cell motility, migration, and invasion of collagen in vitro. In contrast, ppFurin expression in these cells decreased MMP-9 activity and diminished these biological functions, but had no significant effect on TIMP-1 secretion. Taken together, these data showed the specific and opposing roles of Furin and PACE4 in the regulation of MMP-9/TIMP-1-mediated cell motility and invasion.
Lapierre
Marion
M
INSERM U716, Team AVENIR, Institut de Génétique Moléculaire, Université Paris 7, Paris, France.
Siegfried
Geraldine
G
Scamuffa
Nathalie
N
Bontemps
Yannick
Y
Calvo
Fabien
F
Seidah
Nabil G
NG
Khatib
Abdel-Majid
AM
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D045683:Furin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D043484:Proprotein Convertases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D014162:Transfection; D000515:alpha 1-Antitrypsin / Q000235:genetics
D011498:Protein Precursors; D019715:Tissue Inhibitor of Metalloproteinase-1; D000515:alpha 1-Antitrypsin; D003094:Collagen; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C468731:FURIN protein, human; D045683:Furin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9