Cancer Biology, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune-Satara Road, Dhankawadi, Pune, Maharashtra 411043, India.
Department of Pharmaceutical Chemistry, Sinhgad Technical Education Society, Sinhgad College of Pharmacy, Vadgaon (BK), Off Sinhgad Road, Pune, Maharashtra 411041, India.
Brief Bioinform. 2024 Jul 25;25(5). doi: 10.1093/bib/bbae466.
Matairesinol (MAT), a plant lignan renowned for its anticancer properties in hormone-sensitive cancers like breast and prostate cancers, presents a promising yet underexplored avenue in the treatment of metastatic prostate cancer (mPC). To elucidate its specific therapeutic targets and mechanisms, our study adopted an integrative approach, amalgamating network pharmacology (NP), bioinformatics, GeneMANIA-based functional association (GMFA), and experimental validation. By mining online databases, we identified 27 common targets of mPC and MAT, constructing a MAT-mPC protein-protein interaction network via STRING and pinpointing 11 hub targets such as EGFR, AKT1, ERBB2, MET, IGF1, CASP3, HSP90AA1, HIF1A, MMP2, HGF, and MMP9 with CytoHuba. Utilizing DAVID, Gene Ontology (GO) analysis highlighted metastasis-related processes such as epithelial-mesenchymal transition, positive regulation of cell migration, and key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including cancer, prostate cancer, PI3K-Akt, and MAPK signaling, while the web resources such as UALCAN and GEPIA2 affirmed the clinical significance of the top 11 hub targets in mPC patient survival analysis and gene expression patterns. Our innovative GMFA enrichment method further enriched network pharmacology findings. Molecular docking analyses demonstrated substantial interactions between MAT and 11 hub targets. Simulation studies confirmed the stable interactions of MAT with selected targets. Experimental validation in PC3 cells, employing quantitative real-time reverse-transcription PCR and various cell-based assays, corroborated MAT's antimetastatic effects on mPC. Thus, this exhaustive NP analysis, complemented by GMFA, molecular docking, molecular dynamics simulations, and experimental validations, underscores MAT's multifaceted role in targeting mPC through diverse therapeutic avenues. Nevertheless, comprehensive in vitro validation is imperative to solidify these findings.
马胎素（MAT）是一种植物木质素，因其在激素敏感型癌症（如乳腺癌和前列腺癌）中的抗癌特性而备受关注，但在转移性前列腺癌（mPC）的治疗中仍未得到充分探索。为了阐明其具体的治疗靶点和机制，我们采用了一种综合的方法，结合网络药理学（NP）、生物信息学、基于 GeneMANIA 的功能关联（GMFA）和实验验证。通过挖掘在线数据库，我们鉴定了 mPC 和 MAT 的 27 个共同靶点，通过 STRING 构建了 MAT-mPC 蛋白质-蛋白质相互作用网络，并确定了 11 个关键靶点，如 EGFR、AKT1、ERBB2、MET、IGF1、CASP3、HSP90AA1、HIF1A、MMP2、HGF 和 MMP9，利用 CytoHubba 进行分析。通过 DAVID 进行基因本体论（GO）分析，突出了与转移相关的过程，如上皮-间充质转化、细胞迁移的正调控，以及关键的京都基因与基因组百科全书（KEGG）通路，包括癌症、前列腺癌、PI3K-Akt 和 MAPK 信号通路。同时，UALCAN 和 GEPIA2 等网络资源也证实了前 11 个关键靶点在 mPC 患者生存分析和基因表达模式中的临床意义。我们创新性的 GMFA 富集方法进一步丰富了网络药理学的研究结果。分子对接分析表明 MAT 与 11 个关键靶点之间存在大量相互作用。模拟研究证实了 MAT 与选定靶点的稳定相互作用。在 PC3 细胞中的实验验证，采用实时定量逆转录 PCR 和各种基于细胞的检测方法，证实了 MAT 对 mPC 的抗转移作用。因此，本研究通过全面的 NP 分析，结合 GMFA、分子对接、分子动力学模拟和实验验证，强调了 MAT 通过多种治疗途径靶向 mPC 的多效性作用。然而，全面的体外验证对于巩固这些发现至关重要。
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