Theranostics 2019; 9(22):6676-6689. doi:10.7150/thno.34020

Research Paper

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

Han-Li Huang1,2, Yi-Min Liu1, Ting-Yi Sung2, Tsui-Chin Huang3, Ya-Wen Cheng3, Jing-Ping Liou1,4,✉, Shiow-Lin Pan1,2,3,✉

1. TMU Biomedical Commercialization Center, Taipei Medical University, Taipei 11031, Taiwan
2. Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
3. Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
4. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.

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Citation:
Huang HL, Liu YM, Sung TY, Huang TC, Cheng YW, Liou JP, Pan SL. TIMP3 expression associates with prognosis in colorectal cancer and its novel arylsulfonamide inducer, MPT0B390, inhibits tumor growth, metastasis and angiogenesis. Theranostics 2019; 9(22):6676-6689. doi:10.7150/thno.34020. Available from http://www.thno.org/v09p6676.htm

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Abstract

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 TIMP3 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.

Methods: 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 in vivo xenograft model for tumor growth inhibition determination. The anti-metastatic function was validated using a transwell migration assay, and using in vivo lung metastasis and liver metastasis models. The mechanism of MPT0B390-induced TIMP3 expression was further tested using qPCR and Chromatin IP assay. The anti-angiogenesis function was examined by using transwell migration assay, and in vivo Matrigel plug assay.

Results: After screening candidate compounds, we identified MPT0B390 as an effective inducer of TIMP3. We showed that MPT0B390 induces TIMP3 expression significantly and inhibits CRC cell growth in vitro and in vivo. 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 uPA, uPAR, and c-Met. Subsequent Chromatin immunoprecipitation assay revealed that MPT0B390 can significantly inhibit EZH2 expression as well as its binding to TIMP3 promoter region to regulate TIMP3 induction. In addition to the anti-tumor and anti-metastasis capability, MPT0B390 can also induce TIMP3 expression in endothelial cells to inhibit tumor angiogenesis.

Conclusion: These data suggest the potential therapeutic applications of the TIMP3 inducer, MPT0B390, for colorectal cancer treatment.

Keywords: TIMP3, colorectal cancer, arylsulfonamide inducer, MPT0B390.