Urolithins' interaction with hepatocyte growth factor receptor: a mechanistic basis for anticancer activity in...

Gastric adenocarcinoma (GAC) ranks among the most common cancers worldwide. Hepatocyte growth factor receptor, also known as MET, plays crucial roles in GAC progression. Present study aimed to investigate whether urolithin A (UA), urolithin B (UB) and methyl UA (mUA) could induce anticancer effects on GAC cells via targeting MET. For computational analysis, potential molecular targets of urolithins and pathogenic targets of GAC were identified, PPI network was constructed, enrichment analyses were carried out and the expression of MET was assessed in MKN-45 cells. Additionally, pharmacokinetic and druglikeness of urolithins were evaluated, and molecular docking and dynamics simulations were performed. For in vitro analysis, urolithins were synthesized and viability of MKN-45, MG-63 and HFF-3 cells was investigated by alamarBlue assay, followed by apoptosis detection. MET was identified as one of the seven top hub genes for GAC and urolithins, and GO and KEGG enrichment analyses confirmed its involvement in several biological processes and pathways. Volcano plot revealed MET overexpression in MKN-45 cells. Web-based analyses revealed favorable lipophilicity, reasonable water solubility, intestinal absorption, moderate distribution and no significant toxicity concerns for urolithins. Viability assay indicated dose- and cell type-dependent cytotoxicity of urolithins, as the lowest IC₅₀ values belonged to MKN-45 cells, which was confirmed by flow cytometry analysis. Molecular docking demonstrated favorable interactions between UA and UB within the active site of MET. Additionally, molecular dynamics simulations indicated both conformational flexibility and binding stability of UA-MET complex. Our comprehensive study suggests a potential mechanism for anticancer effects of urolithins through interaction with MET in GAC cells.