TIMP3 expression associates with prognosis in colorectal cancer and its novel arylsulfonamide inducer, MPT0B390, inhibits tumor growth, metastasis and angiogenesis.

Tissue inhibitors of metalloproteinase 3 (TIMP3) are a major endogenous inhibitor of matrix metalloproteinase (MMPs) that inhibit tumor growth, invasion, metastasis and angiogenesis. In this study, we found that TIMP3 expression is associated with positive prognosis of colorectal cancer (CRC) clinicopathologically. Therefore, we developed a series of arylsulfonamide derivatives as inducers in order to define potential colorectal cancer therapeutic agent. Among these, MPT0B390 was selected for anti-tumor, anti-metastasis, and anti-angiogenesis property determination. The relationship between TIMP3 expression and clinical pathological features in colorectal patients and cell lines were determined by immunohistochemistry, bioinformatics analysis and western blotting. The anti-tumor function was validated by using MTT, apoptosis pathway detection and xenograft model for tumor growth inhibition determination. The anti-metastatic function was validated using a transwell migration assay, and using lung metastasis and liver metastasis models. The mechanism of MPT0B390-induced expression was further tested using qPCR and Chromatin IP assay. The anti-angiogenesis function was examined by using transwell migration assay, and Matrigel plug assay. After screening candidate compounds, we identified MPT0B390 as an effective inducer of . We showed that MPT0B390 induces expression significantly and inhibits CRC cell growth and . By inducing TIMP3 expression, MPT0B390 can also exert its anti-metastasis effect to inhibit CRC cell migration and invasion and downregulates migration markers such as , , and . Subsequent Chromatin immunoprecipitation assay revealed that MPT0B390 can significantly inhibit EZH2 expression as well as its binding to promoter region to regulate induction. In addition to the anti-tumor and anti-metastasis capability, MPT0B390 can also induce expression in endothelial cells to inhibit tumor angiogenesis. These data suggest the potential therapeutic applications of the inducer, MPT0B390, for colorectal cancer treatment.