title: Dual inhibition of EGFR and c-Met kinase activation by MJ-56 reduces metastasis of HT29 human colorectal cancer cells.
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.
authors.affiliation: Graduate Institute of Molecular Systems Biomedicine, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Hui-Jye
authors.initials: HJ
authors.lastname: Chen
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Jiang
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Lin
authors.forename: Shih-Chang
authors.initials: SC
authors.lastname: Tsai
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Peng
authors.forename: Shinji
authors.initials: S
authors.lastname: Fushiya
authors.forename: Mann-Jen
authors.initials: MJ
authors.lastname: Hour
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D052999:Quinazolinones / Q000008:administration & dosage*; D015398:Signal Transduction; D013343:Styrenes / Q000008:administration & dosage*; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: C585462:6-pyrrolidinyl-2-(3-bromostyryl)quinazolin-4-one; D011799:Quinazolines; D052999:Quinazolinones; D013343:Styrenes; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9