Metalloprotease inhibitors reducing the shedding of human TRAIL

The expression of TNF super family member often undergoes post-translation modifying, including internalization and shedding by specific enzymes. Matrix metalloproteases (MMPs) and proteases containing a disintegrin and a metalloprotease domain (ADAMs) are often responsible for the shedding of these members. But the proteases shedding TNF-related apoptosis inducing ligand (TRAIL, a newly described TNFSF member is still indefinite. Stimulated by IFN-α2a, colon tumor cells colo205 secreted soluble TRAIL (sTRAIL), but the membrane-bound TRAIL (mTRAIL) is not up-regulated accordingly. We found metalloprotease inhibitor 1, 10-phenanthroline and TAPI-1 up-regulted mTRAIL on colo205 cells. The secretion of sTRAIL from colo205 cells stimulated by IFN-α2a was reduced significantly by them also. Endogenous sTRAIL have cytotoxic activity on raji cells, and TAPI-1 reduced cell lysis effect of the supernatant by blocking the shedding of mTRAIL into sTRAIL. In conclusion, metalloprotease inhibitors reducing the shedding of TRAIL.