Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.
Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.
Phytomedicine. 2024 Jun;128:155316. doi: 10.1016/j.phymed.2023.155316. Epub 2023 Dec 25.
Gastric cancer (GC) represents a significant health burden with dire prognostic implications upon metastasis and recurrence. Pterostilbene (PTE) has been proven to have a strong ability to inhibit proliferation and metastasis in other cancers, while whether PTE exhibits anti-GC activity and its potential mechanism remain unclear.
To explore the efficacy and potential mechanism of PTE in treating GC.
We employed a comprehensive set of assays, including CCK-8, EdU staining, colony formation, flow cytometry, cell migration, and invasion assays, to detect the effect of PTE on the biological function of GC cells in vitro. The xenograft tumor model was established to evaluate the in vivo anti-GC activity of PTE. Network pharmacology was employed to predict PTE's potential targets and pathways within GC. Subsequently, Western blotting, immunofluorescence, and immunohistochemistry were utilized to analyze protein levels related to the cell cycle, EMT, and the JAK2/STAT3 pathway.
Our study demonstrated strong inhibitory effects of PTE on GC cells both in vitro and in vivo. In vitro, PTE significantly induced cell cycle arrest at G0/G1 and S phases and suppressed proliferation, migration, and invasion of GC cells. In vivo, PTE led to a dose-dependent reduction in tumor volume and weight. Importantly, PTE exhibited notable safety, leaving mouse weight, liver function, and kidney function unaffected. The involvement of the JAK2/STAT3 pathway in PTE's anti-GC effect was predicted utilizing network pharmacology. PTE suppressed JAK2 kinase activity by binding to the JH1 kinase structural domain and inhibited the downstream STAT3 signaling pathway. Western blotting confirmed PTE's inhibition of the JAK2/STAT3 pathway and EMT-associated protein levels. The anti-GC effect was partially reversed upon STAT3 activation, validating the pivotal role of the JAK2/STAT3 signaling pathway in PTE's activity.
Our investigation validates the potent inhibitory effects of PTE on the proliferation and metastasis of GC cells. Importantly, we present novel evidence implicating the JAK2/STAT3 pathway as the key mechanism through which PTE exerts its anti-GC activity. These findings not only establish the basis for considering PTE as a promising lead compound for GC therapeutics but also contribute significantly to our comprehension of the intricate molecular mechanisms underlying its exceptional anti-cancer properties.
胃癌（GC）是一种严重的健康负担，转移和复发后预后不良。研究已经证明，白藜芦醇（PTE）在其他癌症中具有很强的抑制增殖和转移的能力，然而 PTE 是否具有抗 GC 活性及其潜在机制尚不清楚。
探讨 PTE 治疗 GC 的疗效及潜在机制。
我们采用一系列综合实验，包括 CCK-8、EdU 染色、集落形成、流式细胞术、细胞迁移和侵袭实验，检测 PTE 对 GC 细胞体外生物学功能的影响。建立异种移植肿瘤模型评估 PTE 在体内的抗 GC 活性。采用网络药理学预测 PTE 在 GC 中的潜在靶点和途径。然后，采用 Western blot、免疫荧光和免疫组化分析与细胞周期、EMT 和 JAK2/STAT3 通路相关的蛋白水平。
我们的研究表明 PTE 对 GC 细胞具有很强的抑制作用，无论是在体外还是体内。体外实验中，PTE 显著诱导 GC 细胞周期停滞在 G0/G1 和 S 期，并抑制 GC 细胞的增殖、迁移和侵袭。体内实验中，PTE 导致肿瘤体积和重量呈剂量依赖性减少。重要的是，PTE 表现出显著的安全性，对小鼠体重、肝功能和肾功能没有影响。网络药理学预测 PTE 通过与 JH1 激酶结构域结合抑制 JAK2 激酶活性，从而抑制下游 STAT3 信号通路。Western blot 证实 PTE 抑制 JAK2/STAT3 通路和 EMT 相关蛋白水平。STAT3 激活后部分逆转了 GC 效应，验证了 JAK2/STAT3 信号通路在 PTE 活性中的关键作用。
本研究验证了 PTE 对 GC 细胞增殖和转移的强烈抑制作用。重要的是，我们提出了新的证据，表明 JAK2/STAT3 通路是 PTE 发挥抗 GC 活性的关键机制。这些发现不仅为将 PTE 作为 GC 治疗的有前途的先导化合物奠定了基础，而且对我们理解其卓越抗癌特性的复杂分子机制也具有重要意义。
