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中国癌症防治杂志

中国癌症防治杂志 ›› 2025, Vol. 17 ›› Issue (5): 604-612.doi: 10.3969/j.issn.1674-5671.2025.05.12

• 论著 • 上一篇    下一篇

二甲双胍介导AMPK/KIF1B信号通路抑制膀胱癌细胞转移

  

  1. 广西医科大学生命科学研究院；溶瘤纳米体系开发广西高校工程研究中心；区域性高发肿瘤早期防治研究教育部重点实验室(广西医科大学)；广西医科大学附属肿瘤医院；广西膀胱癌临床医学研究中心；广西零磁肿瘤医学重点实验室
  • 出版日期:2025-10-25 发布日期:2025-12-03
  • 通讯作者: 王琪 E-mail:wangqi@stu.gxmu.edu.cn； 唐勇 E-mail: yong-tang@sr.gxmu.edu.cn
  • 基金资助:
    国家自然科学基金项目（82360587；82560548）；广西科技计划项目重点研发计划（AB25069088）；广西自然科学基金项目（2024GXNSFDA010022；2018GXNSFAA138061）；广西医药领域高层次及骨干人才“139”计划培养项目（G201903036）；南宁市武鸣区科研与技术开发项目（20183203?3）；广西医药卫生适宜技术开发与推广应用项目（S2019052）

Metformin mediates the AMPK/KIF1B signaling pathway to suppress metastasis in bladder cancer cells

  • Online:2025-10-25 Published:2025-12-03

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摘要： 目的 探讨二甲双胍对膀胱癌细胞转移的影响及其对腺苷酸活化蛋白激酶（adenosine monophosphate activated protein kinase，AMPK）/驱动蛋白家族成员1B（kinesin family member 1B，KIF1B）信号通路的调控作用。方法 采用CCK⁃8法和实时无标记细胞分析（real time cellular analysis，RTCA）检测二甲双胍对膀胱癌细胞系SW780、RT4和UMUC3增殖与迁移的影响；通过Western blot分析经二甲双胍处理的膀胱癌细胞中AMPK/P⁃AMPK、mTOR、AKT/P⁃AKT和KIF1B的蛋白表达情况。建立MB49细胞C57BL/6J小鼠肺转移模型，评估二甲双胍对体内转移过程的干预作用及对AMPK和KIF1B表达的调控作用。结果 二甲双胍以浓度依赖性方式降低不同膀胱癌细胞系的增殖能力，其对SW780、RT4和UMUC3的半数抑制浓度（median inhibition concentration，IC50）分别为（26.0±1.4） mmol/L、（32.9±5.3） mmol/L和（20.0±3.4） mmol/L。5 mmol/L二甲双胍处理72 h可显著抑制SW780和UMUC3细胞的迁移（均P<0.05）。在RT4和UMUC3细胞中加入二甲双胍后上调P⁃AMPK蛋白表达，下调KIF1B、AKT和mTOR的蛋白表达。动物实验进一步验证，二甲双胍显著延迟肿瘤形成时间[(34.5±8.3) d vs (24.8±3.7) d，P<0.05]和小鼠的中位生存时间（40 d vs 28 d，P=0.016），且肺转移小鼠模型肺组织中P⁃AMPK蛋白表达升高和KIF1B蛋白表达降低（均P<0.05）。结论 二甲双胍在体内外均能有效抑制膀胱癌细胞的转移行为，其机制可能与激活AMPK通路，进而下调KIF1B表达有关，提示AMPK/KIF1B信号通路在二甲双胍抑制膀胱癌转移过程中具有重要作用。

关键词: 膀胱癌, 二甲双胍, 转移, 腺苷酸活化蛋白激酶, 驱动蛋白家族成员1B

Abstract: Objective To investigate the effect of metformin （MET） in bladder cancer cell metastasis and its regulation on adenosine monophosphate activated protein kinase (AMPK)/kinesin family member 1B (KIF1B) signaling pathway. Methods The effects of MET on the proliferation and migration of bladder cancer cell lines SW780, RT4, and UMUC3 were evaluated using the CCK⁃8 assay and real time cellular analysis (RTCA). The protein expression levels of AMPK/P⁃AMPK, mTOR, AKT/P⁃AKT, and KIF1B in MET⁃treated bladder cancer cells were analyzed via Western blot. Additionally, a lung metastasis model was established in C57BL/6J mice using MB49 cells to assess the intervention effects of MET on the metastasis process in vivo, along with its regulation of AMPK and KIF1B expression. Results MET was found to reduce the proliferation of various bladder cancer cell lines in a concentration⁃dependent manner, with median inhibition concentration （IC50） values of (26.0±1.4) mmol/L, (32.9±5.3) mmol/L, and (20.0±3.4) mmol/L for SW780, RT4, and UMUC3 cell lines, respectively. Treatment with MET at concentrations of 5 mmol/L for 72 hours significantly inhibited the migration of SW780 and UMUC3 cells (all P<0.05). When MET administration upregulated P⁃AMPK protein expression and downregulated KIF1B, AKT, and mTOR protein expression in RT4 and UMUC3 cells. Animal experiments further corroborated MET significantly delayed the formation time of tumor [(34.5±8.3) d vs (24.8±3.7) d， P<0.05）] and the median survival time of mice （40 d vs 28 d， P=0.016）. In addition, the protein expression of P⁃AMPK increased and KIF1B decreased in the lung tissue of lung metastasis mouse models (all P<0.05). Conclusions MET effectively inhibits the metastasis of bladder cancer cells both in vitro and in vivo. This mechanism may involve the activation of the AMPK pathway, which subsequently downregulates the expression of KIF1B, suggesting that the AMPK/KIF1B signaling pathway plays an important role in the MET⁃induced inhibition of bladder cancer metastasis.

Key words: Bladder cancer, Metformin, Metastasis, Adenosine monophosphate activated protein kinase, Kinesin family member 1B

中图分类号: 

  • R737.14