Dual inhibition of EGFR and c-Met kinase activation by MJ-56 reduces metastasis of HT29 human colorectal cancer cells

Chen,Hui-Jye; Jiang,Yi-Lin; Lin,Chung-Ming; Tsai,Shih-Chang; Peng,Shu-Fen; Fushiya,Shinji; Hour,Mann-Jen; Yang,Jai-Sing

doi:10.3892/ijo.2013.1941

Dual inhibition of EGFR and c-Met kinase activation by MJ-56 reduces metastasis of HT29 human colorectal cancer cells

Authors:
- Hui-Jye Chen
- Yi-Lin Jiang
- Chung-Ming Lin
- Shih-Chang Tsai
- Shu-Fen Peng
- Shinji Fushiya
- Mann-Jen Hour
- Jai-Sing Yang
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Affiliations: Graduate Institute of Molecular Systems Biomedicine, China Medical University, Taichung 404, Taiwan, R.O.C., Department of Pharmacology, China Medical University, Taichung 404, Taiwan, R.O.C., Department of Biotechnology, Ming Chuan University, Taoyuan 333, Taiwan, R.O.C., Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, R.O.C., Department of Kampo Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama 362-0806, Japan, School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C.
Published online on: May 16, 2013 https://doi.org/10.3892/ijo.2013.1941
Pages: 141-150

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Abstract

Quinazolinone derivatives are known to possess anticancer activities on cell metastasis and cell death in different human cancer cell lines. Here, we studied the anti-metastasis activity and the underlying mechanisms of the novel quinazoline derivative MJ-56 (6-pyrrolidinyl-2-(3-bromostyryl)quinazolin-4-one). MJ-56 inhibited cell migration and invasion of HT29 human colorectal cancer cells by wound-healing and Matrigel-coated transwell assays in a concentration-dependent manner. MJ-56-treated cells resulted in the reduced expression of matrix metalloproteinase (MMP)-2, -7, -9 and -10 and the reduced enzymatic activities of MMP-2 and MMP-9. In contrast, MJ-56-treated cells enhanced the expression of the tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2. Further analyses showed that MJ-56 attenuated the activities of epidermal growth factor receptor (EGFR), c-Met and the downstream ERK-mediated MAPK and PI3K/AKT/mTOR signaling pathways, which led to decreased protein synthesis by dephosphorylating the translation initiation factors eIF-4B, eIF-4E, eIF-4G and S6 ribosomal protein. In addition, MJ-56 interfered with the NF-κB signaling via impairing PI3K/AKT activation and subsequently reduced the NF-κB-mediated transcription of MMPs. Taken together, the reduced expression of phosphor-EGFR and c-MET is chiefly responsible for all events of blocking metastasis. Our results suggest a potential role of MJ-56 on therapy of colorectal cancer metastasis.

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