Yuan Gang, Mao Jingxin, Li Zheng
Pharmacy Department, Jiulongpo Hospital of Chongqing University of Chinese Medicine, Chongqing Jiulongpo Traditional Chinese Medicine Hospital, Chongqing, 400050, China.
Chongqing Medical and Pharmaceutical College, No. 82, Middle Road of University Town, Shapingba District, Chongqing, 400030, China.
Discov Oncol. 2025 Mar 27;16(1):413. doi: 10.1007/s12672-025-02141-x.
To systematically investigate the mechanism underlying the therapeutic effect of emodin in treatment of prostate cancer.
Combine network pharmacology, molecular docking, molecular dynamics and experimental verification to explored the mechanism. Using the network pharmacology method, through the TCMSP, DisGeNET and Genecards database, the corresponding targets and related signaling pathways of emodin were screened, and emodin and core targets were studied by molecular docking and molecular dynamics uasing Cytoscape 3.7.2 and other software. The biological processes, cellular components and molecular functions of the key targets were determined by GO enrichment analysis. KEGG enrichment analysis identified signaling pathways associated with key targets. GEPIA and Kaplan-Meier database were used to determine the relationship between the expression of core genes in normal people and prostate cancer patients and the prognosis of patients. Cell proliferation inhibition experiment was carried out by MTT method. The mRNA and protein levels of CASP3, TNF, IL1B, TP53, PPARG, and MYC in PC-3 cells were evaluated by RT-PCR and WB method respectively.
There were 31 common targets which closely related to emodin in the treatment of prostate cancer. PPI network analysis showed that MYC, PPARG, TP53, TNF, CASP3, IL1B were the core targets. Go and KEGG enrichment analysis showed that pathways in cancer and IL-17 signaling pathway were the key pathways. Molecular docking and molecular dynamics results indicated that emodin had good binding to prostate cancer and 6 core proteins, and the binding force with TP53 protein was the strongest and most stable. The expression of CASP3 protein in normal people was stronger than that in patients with prostate cancer, and the expression of TP53 protein was closely related to the survival rate of patients with prostate cancer. Experimental verification result revealed that EM significantly increased mRNA expressions of CASP3, PPARG and decreased protein expressions of TNF, TP53, MYC at concentrations ranging from 0.1 to 1.6 μmol/L. Emodin significantly increased protein expressions of CASP3, PPARG and decreased protein expressions of TNF, TP53, MYC, IL1B at concentrations ranging from 10 to 160 µmol/L.
Emodin and TP53 have the best binding and stable conformation among core genes. Emodin exhibits a significant inhibitory effect on PC-3 cells at concentration 0.4 ~ 1.6 μmol/L. It showed that anti-prostate cancer properties by regulating cancer and 1L-17 signaling pathway through up-regulating the expressions of CASP3, PPARG genes/proteins, down-regulating IL1B, TP53, TNF, MYC genes/proteins.
系统研究大黄素治疗前列腺癌的作用机制。
结合网络药理学、分子对接、分子动力学和实验验证来探究其机制。采用网络药理学方法，通过中药系统药理学数据库与分析平台（TCMSP）、疾病基因数据库（DisGeNET）和基因卡片数据库（Genecards）筛选大黄素的相应靶点及相关信号通路，利用Cytoscape 3.7.2等软件通过分子对接和分子动力学研究大黄素与核心靶点。通过基因本体（GO）富集分析确定关键靶点的生物学过程、细胞成分和分子功能。京都基因与基因组百科全书（KEGG）富集分析确定与关键靶点相关的信号通路。利用基因表达谱交互分析（GEPIA）和Kaplan-Meier数据库确定正常人和前列腺癌患者核心基因表达与患者预后的关系。采用MTT法进行细胞增殖抑制实验。分别通过逆转录聚合酶链反应（RT-PCR）和蛋白质免疫印迹法（WB）评估前列腺癌PC-3细胞中半胱天冬酶3（CASP3）、肿瘤坏死因子（TNF）、白细胞介素1β（IL1B）、肿瘤蛋白p53（TP53）、过氧化物酶体增殖物激活受体γ（PPARG）和原癌基因c-Myc（MYC）的mRNA和蛋白水平。
有31个与大黄素治疗前列腺癌密切相关的共同靶点。蛋白质-蛋白质相互作用（PPI）网络分析表明，MYC、PPARG、TP53、TNF、CASP3、IL1B是核心靶点。GO和KEGG富集分析表明，癌症通路和白细胞介素-17信号通路是关键通路。分子对接和分子动力学结果表明，大黄素与前列腺癌及6种核心蛋白具有良好的结合，与TP53蛋白的结合力最强且最稳定。正常人CASP3蛋白表达强于前列腺癌患者，TP53蛋白表达与前列腺癌患者生存率密切相关。实验验证结果显示，在0.1至1.6 μmol/L浓度范围内，大黄素显著增加CASP3、PPARG的mRNA表达，降低TNF、TP53、MYC的蛋白表达。在10至160 μmol/L浓度范围内，大黄素显著增加CASP3、PPARG的蛋白表达，降低TNF、TP53、MYC、IL1B的蛋白表达。
在核心基因中，大黄素与TP53具有最佳结合和稳定构象。大黄素在0.4至1.6 μmol/L浓度下对PC-3细胞具有显著抑制作用。表明大黄素通过上调CASP3、PPARG基因/蛋白表达，下调IL1B、TP53、TNF、MYC基因/蛋白表达，调节癌症和白细胞介素-17信号通路，从而具有抗前列腺癌特性。
