千金藤素在体外通过激活Rap1信号通路抑制膀胱癌细胞的迁移、侵袭和上皮-间质转化。
Cepharanthine inhibits migration, invasion, and EMT of bladder cancer cells by activating the Rap1 signaling pathway in vitro.
作者信息
Chen Bo, Chen Lin, Yang Jin, Hou Mingqiang, Cai Qibo, Dai Wenbin, Zhou Xin, Wang Weiwei, Long Xiaoming, Yin Na
机构信息
Department of Urology, Zunyi Medical University Zunyi 563000, Guizhou, China.
Department of Urology, Clinical Medical College and Affiliated Hospital of Chengdu University Chengdu 610000, Sichuan, China.
出版信息
Am J Transl Res. 2024 May 15;16(5):1602-1619. doi: 10.62347/WDFF7432. eCollection 2024.
BACKGROUND
Cepharanthine, a bioactive constituent of , is known for its potent anti-tumor properties. Nevertheless, the precise impact of this substance on bladder cancer remains poorly comprehended. The aim of this study was to demonstrate the effect and mechanism of cepharanthine on the metastasis of human bladder cancer cells.
METHODS
The application of network pharmacology was utilized to ascertain the possible targets and signaling pathways of cepharanthine in the treatment of bladder cancer. The antiproliferative effects of cepharanthine were evaluated using Cell Counting Kit-8 and colony formation assays. The migration and invasion capabilities were assessed using Transwell assays and wound healing experiments. Proteins related to the Rap1 signaling pathway, cellular migration, cellular invasion, and Epithelial-Mesenchymal Transition (EMT) were quantified by western blotting.
RESULTS
Through database screening, 313 cepharanthine-acting targets, 277 candidate disease targets in bladder cancer, 22 intersecting targets, and 12 core targets were confirmed. The involvement of the Rap1 signaling system was revealed by the Kyoto Encyclopedia of Genes and Genomes' pathway enrichment study. Cepharanthine was shown to decrease bladder cancer cell proliferation, migration, and invasion . Cepharanthine activated the Rap1 signaling pathway by upregulating Epac1 and downregulating E-cadherin and C3G protein expression, leading to increased expression of Rap1 GTP protein and decreased expression of protein kinase D1 and integrin α5. Rap1 signalling pathway activation resulted in the downregulation of migration and invasion-related proteins, matrix metallopeptidase MMP2, MMP9, as well as EMT-related proteins, N-cadherin and Snail, without affecting vimentin expression.
CONCLUSION
Cepharanthine inhibits migration, invasion, and EMT of bladder cancer cells by activating the Rap1 signalling pathway. The results offer helpful insights regarding the possible therapeutic use of cepharanthine for treating bladder cancer.
背景
千金藤素是 的一种生物活性成分，以其强大的抗肿瘤特性而闻名。然而，这种物质对膀胱癌的确切影响仍知之甚少。本研究的目的是证明千金藤素对人膀胱癌细胞转移的作用及机制。
方法
运用网络药理学确定千金藤素治疗膀胱癌的潜在靶点和信号通路。使用细胞计数试剂盒-8和集落形成试验评估千金藤素的抗增殖作用。使用Transwell试验和伤口愈合实验评估迁移和侵袭能力。通过蛋白质印迹法定量与Rap1信号通路、细胞迁移、细胞侵袭和上皮-间质转化（EMT）相关的蛋白质。
结果
通过数据库筛选，确认了313个千金藤素作用靶点、277个膀胱癌候选疾病靶点、22个交叉靶点和12个核心靶点。京都基因与基因组百科全书的通路富集研究揭示了Rap1信号系统的参与。结果表明，千金藤素可降低膀胱癌细胞的增殖、迁移和侵袭能力。千金藤素通过上调Epac1并下调E-钙黏蛋白和C3G蛋白表达来激活Rap1信号通路，导致Rap1 GTP蛋白表达增加，蛋白激酶D1和整合素α5表达降低。Rap1信号通路激活导致迁移和侵袭相关蛋白基质金属蛋白酶MMP2、MMP9以及EMT相关蛋白N-钙黏蛋白和Snail的表达下调，而不影响波形蛋白的表达。
结论
千金藤素通过激活Rap1信号通路抑制膀胱癌细胞的迁移、侵袭和EMT。这些结果为千金藤素治疗膀胱癌的潜在治疗用途提供了有益的见解。
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