Han Bing, Sun Chengtao, Yang Ruiwen, Li Xuan, Kang Jie, Cai Jinyong, Zhou Shuiping, Wang Genbei, Wang Jing, Zhang Jizhou, Sun Yun, Kai Guoyin
Zhejiang Provincial International S&T Cooperation Base for Active Ingredients of Medicinal and Edible Plants and Health, Zhejiang Provincial Key TCM Laboratory for Chinese Resource Innovation and Transformation, Institute of Chinese Medicine Resource Innovation and Quality Evaluation, School of Pharmaceutical Sciences, Jinhua Academy, Zhejiang Chinese Medical University, Hangzhou 310053, China.
National Key Laboratory of Chinese Medicine Modernization, Pharmacology & Toxicology Department of Academy, Tasly Pharmaceuticals Co., Ltd., Tianjin 300410, China.
Phytomedicine. 2025 Sep;145:157023. doi: 10.1016/j.phymed.2025.157023. Epub 2025 Jun 26.
Ovarian cancer is a major lethal malignancy of the female reproductive system. Dihydrotanshinone I (DHT) is a tanshinone compound derived from Salvia miltiorrhiza and possesses significant anti-ovarian cancer activity. However, the mechanism underlying its antitumor effect remains unclear.
This study aimed to evaluate the antitumor effect of DHT on ovarian cancer and elucidate the mechanisms through proteomics analysis.
ES2 ovarian cancer nude mice were established and 4D label-free quantitative proteomics was performed. Bioinformatics analysis, RT-PCR, and western blot were conducted for validation. Further confirmation was achieved by shRNA knockdown, CCK-8 assay, wound healing, transwell, and western blot analysis.
DHT significantly inhibited tumor growth in ES2 xenograft nude mice. Mechanistically, proteomics and GSEA analysis showed that DHT strikingly inhibited pathways related to extracellular matrix (ECM) receptor interaction, cell adhesion molecules, and focal adhesion. RT-PCR and western blot indicated integrin β1 (ITGB1) as a potential target of DHT. DHT downregulated ITGB1 and its downstream effector, focal adhesion kinase (FAK), both in vitro and in vivo. Bioinformatics analysis revealed that high ITGB1 expression correlated with poor prognosis in ovarian cancer patients. Knockdown of ITGB1 markedly inhibited cell viability, wound healing, and migration ability in ES2 cells, and reduced the expression of anti-apoptosis protein Bcl2, ECM proteins FAK, FN1, and cell adhesion protein Claudin1. Additionally, DHT attenuated ECM activator pyrintegrin-induced migration in ES2 cells.
These findings demonstrate that DHT inhibits ovarian tumor growth by suppressing ECM pathway via the ITGB1/FAK axis, highlighting its potential as a therapeutic candidate for ovarian cancer treatment.
卵巢癌是女性生殖系统中一种主要的致死性恶性肿瘤。二氢丹参酮I（DHT）是一种从丹参中提取的丹参酮化合物，具有显著的抗卵巢癌活性。然而，其抗肿瘤作用的机制仍不清楚。
本研究旨在评估DHT对卵巢癌的抗肿瘤作用，并通过蛋白质组学分析阐明其机制。
建立ES2卵巢癌裸鼠模型，并进行4D无标记定量蛋白质组学分析。通过生物信息学分析、RT-PCR和蛋白质免疫印迹法进行验证。通过短发夹RNA敲低、CCK-8检测、伤口愈合实验、Transwell实验和蛋白质免疫印迹分析进一步证实。
DHT显著抑制ES2异种移植裸鼠的肿瘤生长。机制上，蛋白质组学和基因集富集分析表明，DHT显著抑制与细胞外基质（ECM）受体相互作用、细胞粘附分子和粘着斑相关的通路。RT-PCR和蛋白质免疫印迹表明整合素β1（ITGB1）是DHT的潜在靶点。DHT在体外和体内均下调ITGB1及其下游效应分子粘着斑激酶（FAK）。生物信息学分析显示，ITGB1高表达与卵巢癌患者的不良预后相关。敲低ITGB1显著抑制ES2细胞的活力、伤口愈合和迁移能力，并降低抗凋亡蛋白Bcl2、ECM蛋白FAK、FN1和细胞粘附蛋白Claudin1的表达。此外，DHT减弱了ECM激活剂pyrintegrin诱导的ES2细胞迁移。
这些发现表明，DHT通过ITGB1/FAK轴抑制ECM通路来抑制卵巢肿瘤生长，突出了其作为卵巢癌治疗候选药物的潜力。
