Dihydrotanshinone I inhibits ovarian tumor growth by suppressing ITGB1/FAK-mediated extracellular matrix signaling

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-26 DOI:10.1016/j.phymed.2025.157023

Bing Han , Chengtao Sun , Ruiwen Yang , Xuan Li , Jie Kang , Jinyong Cai , Shuiping Zhou , Genbei Wang , Jing Wang , Jizhou Zhang , Yun Sun , Guoyin Kai

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Abstract

Background

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.

Purpose

This study aimed to evaluate the antitumor effect of DHT on ovarian cancer and elucidate the mechanisms through proteomics analysis.

Methods

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.

Results

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.

Conclusion

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.

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二氢丹参酮I通过抑制ITGB1/ fak介导的细胞外基质信号传导抑制卵巢肿瘤生长

背景：卵巢恶性肿瘤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 （Dihydrotanshinone I， DHT）是一种从丹参中提取的丹参酮类化合物，具有显著的抗卵巢癌活性。然而，其抗肿瘤作用的机制尚不清楚。目的探讨二氢睾酮对卵巢癌的抗肿瘤作用，并通过蛋白质组学分析阐明其作用机制。方法建立ses2卵巢癌裸鼠，进行4D无标记定量蛋白质组学分析。采用生物信息学分析、RT-PCR和western blot进行验证。shRNA敲除、CCK-8实验、伤口愈合、transwell和western blot分析进一步证实了这一点。结果dht显著抑制ES2异种移植裸鼠肿瘤生长。在机制上，蛋白质组学和GSEA分析显示DHT显著抑制与细胞外基质（ECM）受体相互作用、细胞粘附分子和局灶粘附相关的途径。RT-PCR和western blot显示整合素β1 （ITGB1）是DHT的潜在靶点。DHT在体外和体内均下调ITGB1及其下游效应物focal adhesion kinase （FAK）。生物信息学分析显示，ITGB1高表达与卵巢癌患者预后不良相关。敲低ITGB1可显著抑制ES2细胞的细胞活力、创面愈合和迁移能力，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可减弱ES2细胞中ECM激活剂pyrintegrin诱导的迁移。结论DHT通过ITGB1/FAK轴抑制ECM通路，从而抑制卵巢肿瘤的生长，提示DHT作为卵巢癌治疗的候选药物具有一定的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.