Metformin Induces G1 Cell Cycle Arrest and Inhibits Cell Proliferation in Nasopharyngeal Carcinoma Cells
Metformin Induces G1 Cell Cycle Arrest and Inhibits Cell Proliferation in Nasopharyngeal Carcinoma Cells
复制标题
DOI：
10.1002/ar.21283
复制
发表时间：
2011-08-01
影响因子：
2
通讯作者：
Bai, Xiao-Chun
中科院分区：
文献类型：
--
作者：
Zhao, Li;Wen, Zhi-Hua;Bai, Xiao-Chun
二甲双胍是一种广泛用于II型糖尿病患者的双胍衍生物，据报道，二甲双胍通过激活AMP活化蛋白激酶（AMPK）对某些癌症具有抗肿瘤活性。但其在鼻咽癌（NPC）中的作用尚不清楚。在此，我们首次报道了1-50 mM二甲双胍以剂量和时间依赖性方式抑制NPC细胞系C666-1中的细胞增殖和集落形成。进一步的研究表明，5 mM二甲双胍处理后，细胞周期蛋白D1的蛋白水平降低，G 0/G1期细胞的百分比增加。二甲双胍还以时间依赖性方式诱导AMPK（T172）的磷酸化。哺乳动物雷帕霉素复合物靶蛋白1（mTORC 1）受AMPK负调控，在细胞生长和增殖中起核心作用，二甲双胍可抑制mTORC 1，表现为其下游靶蛋白40 S核糖体S6激酶1（S6 K1）（T389）的去磷酸化，C666-1细胞中的真核翻译起始因子4 E（eIF 4 E）结合蛋白1（4 E-BP 1）（T37/46）和S6（S235/236）。综上所述，二甲双胍通过下调细胞周期蛋白D1水平并诱导G1细胞周期阻滞来抑制C666-1细胞增殖。AMPK介导的mTORC 1信号转导抑制可能参与了这一过程。Anat Rec，294：1337-1343，2011. (C)2011 Wiley-Liss，Inc.
It has been reported that metformin, a biguanide derivative widely used in type II diabetic patients, has antitumor activities in some cancers by activation of AMP-activated protein kinase (AMPK). But its role in nasopharyngeal carcinoma (NPC) is not known. Here, we reported for the first time that 1-50 mM of metformin in a dose-and time-dependent manner suppressed cell proliferation and colony formation in NPC cell line, C666-1. Further studies revealed that the protein level of cyclin D1 decreased and the percentage of the cells in G0/G1 phase increased by 5 mM metformin treatment. Metformin also induced the phosphorylation of AMPK (T172) in a time-dependent manner. Mammalian target of rapamycin complex 1 (mTORC1), which is negatively regulated by AMPK and plays a central role in cell growth and proliferation, was inhibited by metformin, as manifested by dephosphorylation of its downstream targets 40S ribosomal S6 kinase 1 (S6K1) (T389), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) (T37/46) and S6 (S235/236) in C666-1 cells. In a summary, metformin prevents proliferation of C666-1 cells by down-regulating cyclin D1 level and inducing G1 cell cycle arrest. AMPK-mediated inhibition of mTORC1 signaling may be involved in this process. Anat Rec, 294: 1337-1343, 2011. (C) 2011 Wiley-Liss, Inc.