Diosmetin inhibits the growth and invasion of gastric cancer by interfering with M2 phenotype macrophage polarization

Abstract Overturning M2 phenotype macrophage polarization is a promising therapeutic strategy for gastric cancer (GC). Diosmetin (DIO) is a natural flavonoid with antitumor effect. The aim of this study was to investigate the effect of DIO on polarization of M2 phenotype macrophages in GC. THP‐1 cells were induced to M2 phenotype macrophages and co‐cultured with AGS cells. The effects of DIO were determined by flow cytometry, qRT‐PCR, CCK‐8, Transwell, and western blot. To explore the mechanisms, THP‐1 cells were transfected with adenoviral vectors containing tumor necrosis factor receptor‐associated factor 2 (TRAF2) or si‐TRAF2. DIO (0, 5, 10, and 20 μM) restrained the M2 phenotype macrophage polarization. In addition, DIO (20 μM) reversed the increased viability and invasion of AGS cells induced by the co‐culture of M2 macrophages. Mechanistically, TRAF2 knockdown inhibited the effect of M2 phenotype macrophages on AGS cells' growth and invasion. Furthermore, DIO (20 μM) was found to decrease TRAF2/NF‐κB activity in GC cells. However, TRAF2 overexpressed reversed the inhibitory effect of DIO on the co‐culture system. The in vivo study confirmed that DIO treatment (50 mg/kg) could repress the growth of GC. DIO treatment markedly reduced the expressions of Ki‐67 and N‐cadherin, and decreased the protein levels of TRAF2 and p‐NF‐κB/NF‐κB. In conclusion, DIO inhibited the growth and invasion of GC cells by interfering with M2 phenotype macrophage polarization through repression of the TRAF2/NF‐κB signaling pathway.