A small compound that inhibits tumor necrosis factor-α-induced matrix metalloproteinase-9 upregulation

Abstract

Matrix metalloproteinase-9 (MMP-9) is critically involved in the tumor invasion and metastasis processes. Since TNF-α plays a crucial role in the regulation of MMP-9 expression, the development of molecules capable of modulating TNF-α-induced signaling is an issue of concern. We identified a novel synthetic compound that inhibits TNF-α-induced MMP-9 upregulation in the HT1080 human fibrosarcoma cell line. The active compound SM-7368 inhibited TNF-α-induced MMP-9 upregulation in a concentration-dependent manner and showed maximal activity at 10 μM. SM-7368 inhibited TNF-α-induced MMP-9 mRNA transcript accumulation and protein expression. We also found that SM-7368 strongly inhibits TNF-α-induced NF-κB activity but not AP-1 activity. Moreover, we found that SM-7368 strongly inhibits the TNF-α-induced invasion of HT1080 human fibrosarcoma cell line. Taken together, our results demonstrate that SM-7368 is a synthetic compound that inhibits TNF-α-induced MMP-9 expression, and thus SM-7368 should be useful for the development of chemotherapies targeting TNF-α-mediated tumor invasion and metastasis.

Keywords Matrix metalloproteinase-9; TNF-α; Small compound; NF-κB; Invasion