The Antidiabetic Drug Metformin Inhibits Gastric Cancer Cell Proliferation In Vitro and In Vivo
The Antidiabetic Drug Metformin Inhibits Gastric Cancer Cell Proliferation In Vitro and In Vivo
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DOI：
10.1158/1535-7163.mct-11-0594
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发表时间：
2012-03-01
影响因子：
5.7
通讯作者：
Masaki, Tsutomu
中科院分区：
文献类型：
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作者：
Kato, Kiyohito;Gong, Jian;Masaki, Tsutomu
最近的研究表明，二甲双胍作为双胍家族常用的口服降糖药，可能降低癌症风险并改善预后，但二甲双胍影响包括胃癌在内的各种癌症的机制尚不清楚。本研究的目的是评估二甲双胍对人胃癌细胞体外和体内增殖的影响，并研究与二甲双胍抗肿瘤作用相关的microrna （miRNA）。我们用MKN1、MKN45和MKN74人胃癌细胞株研究二甲双胍对人胃癌细胞的影响。用二甲双胍或不加二甲双胍治疗患有异种移植物肿瘤的胸腺裸鼠。4周后记录肿瘤生长情况，检测细胞周期相关蛋白的表达。此外，我们使用miRNA阵列提示，在体外和体内研究了二甲双胍治疗或不治疗异种移植肿瘤的MKN74细胞中miRNA的差异。二甲双胍在体外抑制MKN1、MKN45和MKN74的增殖。二甲双胍在体外和体内阻断G(0)-G(1)细胞周期。这种阻断伴随着G(1)细胞周期蛋白的强烈减少，特别是在细胞周期蛋白D1，细胞周期蛋白依赖性激酶（Cdk） 4， Cdk6和视网膜母细胞瘤蛋白（Rb）磷酸化的减少。此外，二甲双胍在体外和体内均可降低表皮生长因子受体和胰岛素样生长因子-1受体的磷酸化水平。体外和体内二甲双胍处理显著改变了miRNA的表达。被二甲双胍改变的各种mirna也可能在体内和体外促进肿瘤生长。巨蟹座；11 (3);549 - 60。(c) 2012年aacr。
Recent studies suggest that metformin, which is commonly used as an oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis, but the mechanisms by which metformin affects various cancers, including gastric cancer, remains unknown. The goal of the present study was to evaluate the effects of metformin on human gastric cancer cell proliferation in vitro and in vivo and to study microRNAs (miRNA) associated with antitumor effect of metformin. We used MKN1, MKN45, and MKN74 human gastric cancer cell lines to study the effects of metformin on human gastric cancer cells. Athymic nude mice bearing xenograft tumors were treated with or without metformin. Tumor growth was recorded after 4 weeks, and the expression of cell-cycle-related proteins was determined. In addition, we used miRNA array tips to explore the differences among miRNAs in MKN74 cells bearing xenograft tumors treated with or without metformin in vitro and in vivo. Metformin inhibited the proliferation of MKN1, MKN45, and MKN74 in vitro. Metformin blocked the cell cycle in G(0)-G(1) in vitro and in vivo. This blockade was accompanied by a strong decrease of G(1) cyclins, especially in cyclin D1, cyclin-dependent kinase (Cdk) 4, Cdk6 and by a decrease in retinoblastoma protein (Rb) phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor-1 receptor in vitro and in vivo. The miRNA expression was markedly altered with the treatment of metformin in vitro and in vivo. Various miRNAs altered by metformin also may contribute to tumor growth in vitro and in vivo. Mol Cancer Ther; 11(3); 549-60. (C) 2012 AACR.