杨梅酮通过阻遏HSP90AA1介导的AKT磷酸化抑制膀胱癌细胞的增殖和迁移OA

Objective To explore the targets and molecular mechanisms mediating the inhibitory effect of myricetin against bladder cancer.Methods The potential targets of myricetin were predicted using SwissTargetPrediction and SEA Search Server,bladder cancer-related targets were screened from TCGA transcriptome and FinnGen plasma proteome data,and the intersecting genes were obtained to identify the potential targets.A protein-protein interaction network was constructed,followed by GO and KEGG enrichment analyses.Molecular docking and dynamics simulations were performed to validate the binding between myricetin and the core targets.Amino acid residue virtual mutation was conducted to confirm the binding specificity of myricetin to HSP90AA1.Public single-cell transcriptomic and CRISPR screening data were analyzed to evaluate the cell-type specificity and functional essentiality of HSP90AA1.UM-UC-3 cells were used to examine the effects of myricetin on cell proliferation and migration and expressions of HSP90AA1 and PI3K-AKT pathway proteins.Results Thirty potential targets of myricetin against bladder cancer were obtained,and HSP90AA1 was identified as the central target.KEGG analysis indicated significant enrichment of the target genes in the PI3K-AKT signaling pathway.Molecular docking and dynamics simulations demonstrated high binding affinity and stable conformation between myricetin and HSP90AA1.Bioinformatics analysis suggested that HSP90AA1 was highly and specifically expressed in bladder cancer urothelial cells,and its high expression was correlated with poor progression-free survival of the patients.In UM-UC-3 cells,myricetin concentration-dependently inhibited cell proliferation and migration,and downregulated mRNA level of HSP90AA1 and protein expressions of HSP90AA1,p-PI3K,and p-AKT.Conclusion Myricetin inhibits bladder cancer cell proliferation and migration possibly by targeting HSP90AA1 and regulating the PI3K-AKT signaling pathway,suggesting its potential as a therapeutic agent for bladder cancer.