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

• Published in: International journal of oncology Vol. 43; no. 1; pp. 141 - 150
• Main Authors: CHEN, HUI-JYE, JIANG, YI-LIN, LIN, CHUNG-MING, TSAI, SHIH-CHANG, PENG, SHU-FEN, FUSHIYA, SHINJI, HOUR, MANN-JEN, YANG, JAI-SING
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.07.2013; Spandidos Publications UK Ltd
• Subjects: Angiogenesis; c-Met; Cancer therapies; Cell adhesion & migration; Cell Movement - drug effects; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; EGFR; Epidermal growth factor; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; HT29 Cells; HT29 colorectal cancer cells; Humans; Kinases; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Metastasis; MJ-56; Neoplasm Invasiveness - pathology; Penicillin; Phosphorylation; Proteins; Proto-Oncogene Proteins c-met - biosynthesis; Proto-Oncogene Proteins c-met - metabolism; Quinazolines - pharmacology; Quinazolinones - administration & dosage; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - biosynthesis; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction; Styrenes - administration & dosage; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transcription factors; Transcriptional Activation - drug effects; United States > US
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2013.1941

Quinazolinone derivatives are known to possess anti-cancer 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.