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

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