Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells
Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells
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DOI：
10.1158/0008-5472.can-06-1500
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发表时间：
2006-11-01
期刊：
影响因子：
11.2
通讯作者：
Pollak, Michael
中科院分区：
文献类型：
--
作者：
Zakikhani, Mahvash;Dowling, Ryan;Pollak, Michael
最近的人群研究提供了一些线索，表明二甲双胍的使用可能与某些癌症的发病率降低和预后改善有关。这种药物被广泛用于治疗2型糖尿病，常被称为“胰岛素增敏剂”，因为它不仅能降低血糖，还能降低与胰岛素抵抗相关的高胰岛素血症。由于胰岛素和胰岛素样生长因子刺激许多正常和转化的细胞类型的增殖，通过这些受体促进信号传递的药物有望促进增殖。我们在这里表明，二甲双胍作为一种生长抑制物，而不是胰岛素增敏剂对上皮细胞起作用。针对AMP激酶的小干扰RNA可以保护乳腺癌细胞免受二甲双胍诱导的生长抑制。这表明，最近被证明是二甲双胍抑制肝细胞糖异生所必需的AMP激酶途径的激活，也参与了二甲双胍诱导的上皮细胞生长抑制。这种生长抑制与雷帕霉素和S6激酶激活的哺乳动物靶标减少以及mRNA翻译的普遍减少有关。这些结果证明了MAV有助于二甲双胍的抗肿瘤作用的机制，最近的人口研究表明，并证明了进一步的工作，以探索AMP激酶激活剂在癌症预防和治疗中的潜在作用。
Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an "insulin sensitizer" because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase. This shows that AMP kinase pathway activation by metformin, recently shown to be necessary for metformin inhibition of gluconeogenesis in hepatocytes, is also involved in metformin-induced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that maV contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment.