Anti-tumour effect of metformin in canine mammary gland tumour cells
Anti-tumour effect of metformin in canine mammary gland tumour cells
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DOI：
10.1016/j.tvjl.2015.04.026
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发表时间：
2015-08-01
影响因子：
2.2
通讯作者：
Nakagawa, T.
中科院分区：
文献类型：
--
作者：
Saeki, K.;Watanabe, M.;Nakagawa, T.
二甲双胍是一种口服降糖药，用于治疗 2 型糖尿病。据报道其药理活性涉及线粒体呼吸复合物I，线粒体呼吸复合物抑制剂对转移性犬乳腺肿瘤（CMGT）细胞系的生长具有很强的抑制作用。据推测，二甲双胍对转移性 CMGT 细胞具有选择性抗肿瘤作用。本研究的目的是研究二甲双胍对具有不同转移潜能的两种 CMGT 克隆细胞系的细胞生长、ATP 和活性氧 (ROS) 产生以及 AMP 激活蛋白激酶 (AMPK) 哺乳动物雷帕霉素靶蛋白 (mTOR) 通路的体外影响。此外，转录组分析用于确定二甲双胍破坏的细胞过程，并在小鼠异种移植模型中检查体内抗肿瘤作用。二甲双胍在体外抑制 CMGT 细胞生长，转移性克隆 (CHMp-5b) 显示出更高的敏感性。二甲双胍暴露后，在转移性和非转移性 (CHMp-13a) 细胞系中观察到 ATP 耗尽和 ROS 升高程度相似。然而，随后的 AMPK 激活和 mTOR 通路抑制仅在二甲双胍不敏感的非转移细胞中较为突出。微阵列分析显示二甲双胍处理 CHMp-5b 细胞可抑制细胞周期进程，蛋白质印迹和细胞周期分析进一步证实了这一点。此外，二甲双胍显着抑制异种移植的转移性 CMGT 细胞中的肿瘤生长。总之，二甲双胍通过 AMPK 独立的细胞周期阻滞在转移性 CMGT 细胞中表现出抗肿瘤作用。其作用机制在非转移性克隆中有所不同，观察到 AMPK 激活和 mTOR 抑制。 (C) 2015 Elsevier Ltd. 保留所有权利。
Metformin is an oral hypoglycaemic drug used in type 2 diabetes. Its pharmacological activity reportedly involves mitochondrial respiratory complex I, and mitochondrial respiratory complex inhibitors have a strong inhibitory effect on the growth of metastatic canine mammary gland tumour (CMGT) cell lines. It is hypothesised that metformin has selective anti-tumour effects on metastatic CMGT cells. The aim of this study was to investigate the in vitro effect of metformin on cell growth, production of ATP and reactive oxygen species (ROS), and the AMP-activated protein kinase (AMPK) mammalian target of rapamycin (mTOR) pathway in two CMGT clonal cell lines with different metastatic potential. In addition, transcriptome analysis was used to determine cellular processes disrupted by metformin and in vivo anti-tumour effects were examined in a mouse xenograft model.Metformin inhibited CMGT cell growth in vitro, with the metastatic clone (CHMp-5b) displaying greater sensitivity. ATP depletion and ROS elevation were observed to a similar extent in the metastatic and non-metastatic (CHMp-13a) cell lines after metformin exposure. However, subsequent AMPK activation and mTOR pathway inhibition were prominent only in metformin-insensitive non-metastatic cells. Microarray analysis revealed inhibition of cell cycle progression by metformin treatment in CHMp-5b cells, which was further confirmed by Western blotting and cell cycle analysis. Additionally, metformin significantly suppressed tumour growth in xenografted metastatic CMGT cells. In conclusion, metformin exhibited an anti-tumour effect in metastatic CMGT cells through AMPK-independent cell cycle arrest. Its mechanism of action differed in the non-metastatic clone, where AMPK activation and mTOR inhibition were observed. (C) 2015 Elsevier Ltd. All rights reserved.