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 mum, matrix metalloprot einase (MMP)-2 activity with an approximate IC50 of 2 mum but did not inhib it MMP-9 activity. This differential capacity of Trx to inhibit TIMP and MM P activity resulted in the promotion of MMP-2 and MMP-9 activity in the pre sence of molar TIMP excess. Inhibition of TIMP and MMP-2 activity by Trx wa s dependent upon thioredoxin reductase (TrxR), was abolished by Trx catalyt ic site mutation and did not result from TIMP or MMP-2 degradation. HepG2 h epatocellular carcinoma cells induced to secrete Trx inhibited TIMP activit y 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 S K-N-SH invasive capacity in vitro in the absence of exogenous TrxR. This st udy therefore identifies a novel extracellular role for the thioredoxin/thi oredoxin reductase redox system in the differential inhibition of TIMP and MMP activity and provides a novel mechanism for altering the TIMP/MMP balan ce that is of potential relevance to tumor invasion.