Thioredoxin alters the matrix metalloproteinase/tissue inhibitors of metalloproteinase balance and stimulates human SK‐N‐SH neuroblastoma cell invasion

• Published in: European journal of biochemistry Vol. 268; no. 2; pp. 405 - 413
• Main Authors: Farina, Antonietta R., Tacconelli, Antonella, Cappabianca, Lucia, Masciulli, Maria‐Paola, Holmgren, Arne, Beckett, Geoffery J., Gulino, Alberto, Mackay, Andrew R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-01-2001
• Subjects: Disulfides - metabolism; Humans; invasion; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors; Medicin och hälsovetenskap; metalloproteinase; Neoplasm Invasiveness; Neoplasm Proteins - metabolism; Neoplasm Proteins - pharmacology; Neuroblastoma - pathology; thioredoxin; thioredoxin reductase; Thioredoxin-Disulfide Reductase - metabolism; Thioredoxins - metabolism; Thioredoxins - pharmacology; Tissue Inhibitor of Metalloproteinase-1 - antagonists & inhibitors; Tissue Inhibitor of Metalloproteinase-2 - antagonists & inhibitors; tissue inhibitor of metalloproteinases; Tissue Inhibitor of Metalloproteinases - antagonists & inhibitors; Tumor Cells, Cultured
• ISSN: 0014-2956; 1432-1033
• DOI: 10.1046/j.1432-1033.2001.01892.x

Thioredoxin (Trx) inhibited tissue inhibitor of metalloproteinase (TIMP)‐1 and TIMP‐2 activity with an approximate IC50 of 0.3 µm, matrix metalloproteinase (MMP)‐2 activity with an approximate IC50 of 2 µm 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.