Wei Shihui, Zhang Jing, Wu Hai, Liao Zhengguang, Liu Zhengrui, Hou Yuhang, Du Danyu, Jiang Jingwei, Sun Li, Yuan Shengtao, Yang Mei
New Drug Screening and Pharmacodynamics Evaluation Center, National Key Laboratory for Multi-Target Natural Drugs, China Pharmaceutical University, Nanjing 210009, China.
Pharmaceutics. 2024 Dec 21;16(12):1620. doi: 10.3390/pharmaceutics16121620.
: Gastric cancer (GC) is the leading cause of cancer-related deaths worldwide. C118P, a microtubule inhibitor with anti-angiogenic and vascular-disrupting activities, was proven to be cytotoxic to various cancer cell lines. This study aimed to explore the anti-tumor effect of C118P against gastric cancer and identify its potential target. : The MTT assay, colony formation assay, and EdU incorporation assay were used to evaluate the effect of C118P on GC cell proliferation. Cell cycle and cell apoptosis were measured using flow cytometry. Molecular docking, a microscale thermophoresis (MST) analysis, and the cellular thermal shift assay (CETSA) were used to investigate the binding of C118P to RAB1A. Autophagy-related effects were evaluated by using the MDC staining assay, immunofluorescence assay, and immunoblotting assay. The SGC-7901 cell line xenograft mouse model was used to confirm the anti-tumor efficacy of C118P. : C118P dramatically inhibited proliferation, induced G2/M cell cycle arrest, and triggered apoptosis in GC cell lines HGC-27 and SGC-7901. Mechanistically, C118P was demonstrated to bind with RAB1A and reduce the RAB1A protein level, accompanied by the inhibition of mTORC1 signaling. Moreover, C118P induced autophagosome formation and promoted RAB1A protein degradation in an autophagy-lysosomal-dependent manner. The in vivo study verified that C118P inhibits GC growth by inhibiting the RAB1A-mTOR axis. : Our findings suggested that C118P inhibits GC growth by promoting the autophagy-lysosomal-dependent degradation of RAB1A and modulating mTOR C1 signaling. C118P shows potential as being a small molecule drug effective in the treatment of gastric cancer via targeting RAB1A.
胃癌（GC）是全球癌症相关死亡的主要原因。C118P是一种具有抗血管生成和血管破坏活性的微管抑制剂，已被证明对多种癌细胞系具有细胞毒性。本研究旨在探讨C118P对胃癌的抗肿瘤作用并确定其潜在靶点。：采用MTT法、集落形成试验和EdU掺入试验评估C118P对GC细胞增殖的影响。使用流式细胞术测量细胞周期和细胞凋亡。采用分子对接、微量热泳动（MST）分析和细胞热位移试验（CETSA）研究C118P与RAB1A的结合。通过MDC染色试验、免疫荧光试验和免疫印迹试验评估自噬相关效应。使用SGC - 7901细胞系异种移植小鼠模型确认C118P的抗肿瘤疗效。：C118P显著抑制HGC - 27和SGC - 7901胃癌细胞系的增殖，诱导G2/M期细胞周期阻滞并引发凋亡。机制上，C118P被证明与RAB1A结合并降低RAB1A蛋白水平，同时抑制mTORC1信号传导。此外，C118P以自噬 - 溶酶体依赖性方式诱导自噬体形成并促进RAB1A蛋白降解。体内研究证实C118P通过抑制RAB1A - mTOR轴抑制GC生长。：我们的研究结果表明，C118P通过促进RAB1A的自噬 - 溶酶体依赖性降解和调节mTOR C1信号传导来抑制GC生长。C118P显示出作为一种通过靶向RAB1A有效治疗胃癌的小分子药物的潜力。
