Hosseini Fatemehsadat, Ahmadi Abdolreza, Nasiri Sarvi Zahra, Iranshahy Milad, Rassouli Fatemeh B
Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Discov Oncol. 2025 May 1;16(1):651. doi: 10.1007/s12672-025-02444-z.
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 IC 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.
胃腺癌（GAC）是全球最常见的癌症之一。肝细胞生长因子受体，也称为MET，在GAC进展中起关键作用。本研究旨在探讨尿石素A（UA）、尿石素B（UB）和甲基尿石素A（mUA）是否可通过靶向MET对GAC细胞产生抗癌作用。进行计算分析时，确定了尿石素的潜在分子靶点和GAC的致病靶点，构建了蛋白质-蛋白质相互作用（PPI）网络，进行了富集分析，并评估了MKN-45细胞中MET的表达。此外，还评估了尿石素的药代动力学和类药性，并进行了分子对接和动力学模拟。进行体外分析时，合成了尿石素，通过alamarBlue检测法研究了MKN-45、MG-63和HFF-3细胞的活力，随后进行凋亡检测。MET被确定为GAC和尿石素的七个顶级枢纽基因之一，基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析证实其参与了多个生物学过程和通路。火山图显示MKN-45细胞中MET过表达。基于网络的分析表明，尿石素具有良好的亲脂性、合理的水溶性、肠道吸收性、适度的分布性且无明显毒性问题。活力检测表明尿石素具有剂量和细胞类型依赖性细胞毒性，因为最低半数抑制浓度（IC）值属于MKN-45细胞，流式细胞术分析证实了这一点。分子对接表明UA和UB在MET活性位点内具有良好的相互作用。此外，分子动力学模拟表明UA-MET复合物具有构象灵活性和结合稳定性。我们的综合研究提出了尿石素通过与GAC细胞中的MET相互作用产生抗癌作用的潜在机制。
