Thioredoxin alters the matrix metalloproteinase/tissue inhibitors of metalloproteinase balance and stimulates human SK-N-SH neuroblastoma cell invasion.
Thioredoxin (Trx) inhibited tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 activity with an approximate IC50 of 0.3 microM, matrix metalloproteinase (MMP)-2 activity with an approximate IC50 of 2 microM but did not inhibit MMP-9 activity. This differential capacity of Trx to inhibit TIMP and MMP activity resulted in the promotion of MMP-2 and MMP-9 activity in the presence of molar TIMP excess. Inhibition of TIMP and MMP-2 activity by Trx was dependent upon thioredoxin reductase (TrxR), was abolished by Trx catalytic site mutation and did not result from TIMP or MMP-2 degradation. HepG2 hepatocellular carcinoma cells induced to secrete Trx inhibited TIMP activity in the presence of TrxR. SK-N-SH neuroblastoma cells secreted TrxR, which inhibited TIMP and MMP-2 activity in the presence of Trx. Trx stimulated SK-N-SH invasive capacity in vitro in the absence of exogenous TrxR. This study therefore identifies a novel extracellular role for the thioredoxin/thioredoxin reductase redox system in the differential inhibition of TIMP and MMP activity and provides a novel mechanism for altering the TIMP/MMP balance that is of potential relevance to tumor invasion.
Farina
A R
AR
Section of Molecular Pathology, Department of Experimental Medicine, University of L'Aquila, Via Vetoio, Coppito II, 61700 L'Aquila, Italy.
Tacconelli
A
A
Cappabianca
L
L
Masciulli
M P
MP
Holmgren
A
A
Beckett
G J
GJ
Gulino
A
A
Mackay
A R
AR
D004220:Disulfides / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000037:antagonists & inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000037:antagonists & inhibitors; D019714:Tissue Inhibitor of Metalloproteinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D004220:Disulfides; D061965:Matrix Metalloproteinase Inhibitors; D009363:Neoplasm Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase; D020780:Matrix Metalloproteinase 9