Network-pharmacology-based identification of caveolin-1 as a key target of Oldenlandia diffusa to suppress breast cancer metastasis
Network-pharmacology-based identification of caveolin-1 as a key target of Oldenlandia diffusa to suppress breast cancer metastasis
复制标题
基于网络药理学鉴定 Caveolin-1 是白花蛇舌草抑制乳腺癌转移的关键靶点。
DOI：
10.1016/j.biopha.2019.108607
复制
发表时间：
2019
影响因子：
7.5
通讯作者：
Wang Zhiyu
中科院分区：
文献类型：
--
作者：
Yang Bowen;Wang Neng;Wang Shengqi;Li Xiong;Zheng Yifeng;Li Min;Song Juxian;Zhang Fengxue;Mei Wenjie;Lin Yi;Wang Zhiyu
背景乳腺癌仍是女性最常见的恶性肿瘤，转移是导致乳腺癌患者死亡的首要原因。白花蛇舌草作为转移性乳腺癌患者的辅助治疗手段，已被中医广泛应用，并取得了良好的疗效。方法通过多分子生物学实验和网络药理学、生物信息学分析，探讨白花蛇舌草抗乳腺癌转移的机制。结果白花蛇舌草乙醇提取物(EEOD)对高转移乳腺癌细胞株MDA-MB-231和MDA-MB-453有明显的抑制增殖和诱导凋亡作用，而对多种非恶性细胞无明显的细胞毒作用。此外，EEOD通过调节基质金属蛋白酶(MMPs)和上皮-间充质转化(EMT)通路，显著抑制上述乳腺癌细胞的迁移和侵袭能力。更重要的是，EEOD还能显著抑制斑马鱼体内异种移植模型中乳腺癌的转移。网络药理学和生物信息学分析进一步表明，EEOD产生了12个候选化合物和225个潜在靶点，并分享了85个与乳腺癌转移相关的推定靶点。从机理上，RNA测序和实验验证结果表明，EEOD可能通过抑制小窝蛋白-1(Cav-1)的表达来抑制乳腺癌的转移，因为过表达Cav-1可以削弱EEOD的抗转移作用。结论总之，我们的研究结果证明EEOD通过抑制Cav-1的表达而抑制乳腺癌的转移，为EEOD作为转移性乳腺癌患者的辅助治疗奠定了基础。本研究还为网络药理学和生物信息学分析提供了新的见解，作为阐明中医药科学基础的有效工具。
BackgroundBreast cancer remains the most common female malignancy and metastasis is the leading cause of death in breast cancer patients.Oldenlandia diffusahas been empirically and extensively used as an adjuvant therapy for metastatic breast cancer patients in Traditional Chinese Medicine (TCM) with proven efficacy. However, its anti-metastasis mechanism has been poorly revealed.MethodsMultiple molecular biology experiments as well as network pharmacology, bioinformatics analysis were conducted to investigate the anti-metastasis mechanism ofOldenlandia diffusain breast cancer.ResultsWe demonstrated that ethanol extract ofOldenlandia diffusa(EEOD) significantly inhibited proliferation and induced apoptosis of high-metastatic breast cancer cell lines MDA-MB-231 and MDA-MB-453, while having no obvious cytotoxic effect on multiple nonmalignant cells. Furthermore, EEOD remarkably suppressed the migration and invasion capacities of the above breast cancer cells by modulating the matrix metalloproteinases (MMPs) and the epithelial-mesenchymal transition (EMT) pathway. More importantly, EEOD also significantly inhibited breast cancer metastasis in zebrafish xenotransplantation modelin vivo. Network pharmacology and bioinformatics analysis further demonstrated that EEOD yielded 12 candidate compounds and 225 potential targets, and shared 85 putative targets associated with breast cancer metastasis. Mechanistically, RNA sequencing and experimental validation results suggested that EEOD might inhibit breast cancer metastasis by attenuating the expression of caveolin-1 (Cav-1) as overexpression of Cav-1 could weaken the anti-metastasis efficacy of EEOD.ConclusionsOverall, our findings proved that EEOD could inhibit breast cancer metastasis by attenuating the expression of Cav-1, highlighting the use of EEOD as an adjunctive therapy for metastatic breast cancer patients. This study also provides novel insights into network pharmacology and bioinformatics analysis as effective tools to illuminate the scientific basis of TCM.