Foretinib Inhibits Cancer Stemness and Gastric Cancer Cell Proliferation by Decreasing CD44 and c-MET Signaling.

Abstract

PurposeCD44 isoforms are highly expressed in cancer stem cells, initiating tumor growth and sustaining tumor self-renewal. Among these isoforms, CD44 variant 9 (CD44v9) is overexpressed in chronic inflammation-induced cancer. CD44 and the mesenchymal-to-epithelial transition (MET) receptor tyrosine kinase are coactivated in some gastric cancers (GCs). In this study, we characterized MET and CD44 expression and signaling in human GC cell lines and analyzed differences in the susceptibility of these lines to foretinib.Patients and MethodsWe analyzed cell viability and the rate of apoptotic cells using MTS assays and flow cytometry, respectively. Gene and protein expression were assessed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunoblotting, respectively.ResultsForetinib treatment resulted in dose-dependent inhibition of growth in c-MET-amplified MKN45 and SNU620 cells with concomitant induction of apoptosis, but not in c-MET-reduced MKN28 and AGS cells. Foretinib treatment also significantly reduced phosphor-c-MET, phosphor-AKT, beta-catenin, and COX-2 protein expression in MKN45 and SNU620 cells. Interestingly, foretinib significantly reduced CD44, CD44v9, COX-2, OCT3/4, CCND1, c-MYC, VEGFA, and HIF-1a gene expression in CD44 and MET coactivated MKN45 cells and increased CD44s gene expression; in contrast, these drugs were only slightly active against SNU620 cells.ConclusionThe results of this study indicate that foretinib could be a therapeutic agent for the prevention or treatment of GCs positive for CD44v9 and c-MET.