船形乌头硷通过靶向 AURKA-β-catenin/Akt/STAT3 和细胞周期通路抑制胃癌发生。

Securinine inhibits carcinogenesis in gastric cancer by targeting AURKA-β-catenin/Akt/STAT3 and the cell cycle pathway.

机构信息

Department of Gastroenterology, Cancer Hospital Affiliated to Shanxi Medical University/Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, PR China; The Second Clinical Medical College, Shanxi Medical University, Taiyuan, PR China.

The Second Clinical Medical College, Shanxi Medical University, Taiyuan, PR China; Department of Orthopedics, The Second People's Hospital of Changzhi, Changzhi, PR China.

出版信息

Phytomedicine. 2024 Jul 25;130:155735. doi: 10.1016/j.phymed.2024.155735. Epub 2024 May 17.

DOI:10.1016/j.phymed.2024.155735

PMID:38810557

Abstract

BACKGROUND

Gastric cancer (GC) is difficult to treat with currently available treatments. Securinine (SCR) has a lengthy history of use in the treatment of disorders of the nervous system, and its anticancer potential has been gaining attention in recent years. The aim of this study was to explore the repressive effect of SCR on GC and its fundamental mechanism.

METHODS

The efficacy of SCR in GC cells was detected by MTT assays. Colony formation, flow cytometry and Transwell assays were used to assess the changes in the proliferation, apoptosis, cell cycle distribution, migration and invasion of GC cells after treatment. AGS (human gastric carcinoma cell)-derived xenografts were used to observe the effect of SCR on tumor growth in vivo. The molecular mechanism of action of SCR in GC was explored via RNA sequencing, bioinformatics analysis, Western blotting, molecular docking, and immunohistochemistry.

RESULTS

SCR was first discovered to inhibit the proliferation, migration, and invasion of GC cells while initiating apoptosis and cell cycle arrest in vitro. It was also established that SCR has excellent anticancer effects in vivo. Interestingly, AURKA acts as a crucial target of SCR, and AURKA expression can be blocked by SCR. Moreover, this study revealed that SCR suppresses the cell cycle and the β-catenin/Akt/STAT3 pathways, which were previously reported to be regulated by AURKA.

CONCLUSION

SCR exerts a notable anticancer effect on GC by targeting AURKA and blocking the cell cycle and β-catenin/Akt/STAT3 pathway. Thus, SCR is a promising pharmacological option for the treatment of GC.

摘要

背景

胃癌（GC）目前的治疗方法效果有限。水苏碱（SCR）在治疗神经系统疾病方面已有悠久的应用历史，近年来其抗癌潜力受到关注。本研究旨在探讨 SCR 对 GC 的抑制作用及其基本机制。

方法

通过 MTT 法检测 SCR 在 GC 细胞中的疗效。通过集落形成、流式细胞术和 Transwell 分析评估 SCR 处理后 GC 细胞增殖、凋亡、细胞周期分布、迁移和侵袭的变化。AGS（人胃癌细胞）衍生异种移植模型用于观察 SCR 对体内肿瘤生长的影响。通过 RNA 测序、生物信息学分析、Western blot、分子对接和免疫组化探讨 SCR 在 GC 中的作用机制。

结果

SCR 首先被发现可抑制 GC 细胞的增殖、迁移和侵袭，同时诱导细胞凋亡和细胞周期阻滞。体内实验也证实了 SCR 具有良好的抗癌作用。有趣的是，AURKA 是 SCR 的关键靶标，SCR 可阻断 AURKA 的表达。此外，本研究还揭示了 SCR 可抑制细胞周期和β-catenin/Akt/STAT3 通路，这些通路之前被报道受 AURKA 调节。