Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin
Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin
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DOI：
10.1158/0008-5472.can-12-2907
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发表时间：
2012-12-01
期刊：
影响因子：
11.2
通讯作者：
Pollak, Michael N.
中科院分区：
文献类型：
--
作者：
Javeshghani, Shiva;Zakikhani, Mahvash;Pollak, Michael N.
流行病学和实验数据已经导致对双胍类在癌症预防和/或治疗中的可能作用的兴趣增加。既往研究表明，二甲双胍的主要作用是抑制氧化磷酸化，导致线粒体ATP生成减少和AMPK活化。在体外，这可能会导致AMPK依赖性的生长抑制，如果AMPK及其效应途径是完整的，或一个充满活力的危机，如果这些是有缺陷的。我们现在发现，几种转化细胞系暴露于二甲双胍的影响因碳源而异：在存在谷氨酰胺和不存在葡萄糖的情况下，细胞ATP减少75%和细胞数量减少80%是典型的;相反，当存在葡萄糖时，二甲双胍暴露导致糖酵解增加，ATP水平和细胞数量仅适度减少。myc的过度表达与二甲双胍抗增殖作用的敏感性相关，这与myc参与“谷氨酰胺成瘾”一致。我们的研究结果揭示了以前未认识到的影响二甲双胍敏感性的因素，并表明二甲双胍诱导的糖酵解增加减弱了化合物的抗增殖作用。Cancer Res; 72（23）; 6257-67. (C)2012年AACR。
Epidemiologic and experimental data have led to increased interest in possible roles of biguanides in cancer prevention and/or treatment. Prior studies suggest that the primary action of metformin is inhibition of oxidative phosphorylation, resulting in reduced mitochondrial ATP production and activation of AMPK. In vitro, this may lead to AMPK-dependent growth inhibition if AMPK and its effector pathways are intact or to an energetic crisis if these are defective. We now show that the effect of exposure of several transformed cell lines to metformin varies with carbon source: in the presence of glutamine and absence of glucose, a 75% decrease in cellular ATP and an 80% decrease in cell number is typical; in contrast, when glucose is present, metformin exposure leads to increased glycolysis, with only a modest reduction in ATP level and cell number. Overexpression of myc was associated with sensitization to the antiproliferative effects of metformin, consistent with myc involvement in "glutamine addiction". Our results reveal previously unrecognized factors that influence metformin sensitivity and suggest that metformin-induced increase in glycolysis attenuates the antiproliferative effects of the compound. Cancer Res; 72(23); 6257-67. (C) 2012 AACR.