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.

journal_name

Int J Oncol

authors

Chen HJ,Jiang YL,Lin CM,Tsai SC,Peng SF,Fushiya S,Hour MJ,Yang JS

doi

10.3892/ijo.2013.1941

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

141-50

issue

1

eissn

1019-6439

issn

1791-2423

journal_volume

43

pub_type

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