Abstract
Anomalous changes of the cell mesenchymal–epithelial transition factor (c-Met) receptor tyrosine kinase signaling pathway play an important role in the occurrence and development of human cancers, including gastric cancer. In this study, we designed and synthesized a novel peptide (CM 7) targeting the tyrosine kinase receptor c-Met, that can inhibit c-Met-mediated signaling in MKN-45 and U87 cells. Its affinity to human c-Met protein or c-Met-positive cells was determined, which showed specific binding to c-Met with high affinity. Its biological activities against MKN-45 c-Met-positive cells were evaluated in vitro and in vivo. As a result, peptide CM 7 exhibited moderate regulation of c-Met-mediated cell proliferation, migration, invasion, and scattering. The inhibitory effect of peptide CM 7 on tumor growth in vivo was investigated by establishing a xenograft mouse model using MKN-45 cells, and the growth inhibition rate of tumor masses for peptide CM 7 was 62%. Based on our data, CM 7 could be a promising therapeutic peptide for c-Met-dependent cancer patients.
Highlights
The cell mesenchymal–epithelial transition factor (c-Met), referred to as MET or hepatocyte growth factor (HGF) receptor, belongs to a subfamily of receptor tyrosine kinases (RTKs) and is a transmembrane protein encoded by the MET proto-oncogene [1]
Relevant studies have found that abnormal activation of the c-Met signaling pathway is induced and regulated by HGF, and studies have reported that the immunoglobulin-like region, especially
in the plexins and transcription factors (IPT) 3 and 4, or the Sema domain of c-Met plays a crucial role in the aberrant activation of this signaling pathway [6]
Summary
The cell mesenchymal–epithelial transition factor (c-Met), referred to as MET or hepatocyte growth factor (HGF) receptor, belongs to a subfamily of receptor tyrosine kinases (RTKs) and is a transmembrane protein encoded by the MET proto-oncogene [1]. It is a heterodimer linked by a disulfide bond between a 50 kDa α subunit and a 145 kDa β subunit [2,3]. In the extracellular region of the c-Met protein, the PSI domain is connected by four IPT domains to the transmembrane helix of MET and the intracellular kinase domain. The specific role of the IPT domain in the c-Met signaling pathway is still unclear, but it has been reported that the IPT domain of c-Met plays an important role in the activation of c-Met kinase, especially the fourth IPT domain [5,6]
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