Effects of metformin on cell growth and AMPK activity in pituitary adenoma cell cultures, focusing on the interaction with adenylyl cyclase activating signals
Effects of metformin on cell growth and AMPK activity in pituitary adenoma cell cultures, focusing on the interaction with adenylyl cyclase activating signals
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DOI：
10.1016/j.mce.2017.09.030
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发表时间：
2018-07-15
影响因子：
4.1
通讯作者：
Tulipano, Giovanni
中科院分区：
文献类型：
--
作者：
Faggi, Lara;Giustina, Andrea;Tulipano, Giovanni
几年来，我们一直在研究AMP活化蛋白激酶（AMPK）作为GH分泌型垂体腺瘤药物治疗的靶点。本研究的目的是研究二甲双胍对大鼠垂体腺瘤细胞生长和相关细胞信号通路的直接影响，二甲双胍可导致不同细胞类型中AMPK的激活。我们的研究结果表明，二甲双胍可以通过AMPK激活介导的大鼠垂体瘤细胞的生长抑制活性，尽管最有可能涉及多种机制。膜蛋白，包括生长因子受体，是AMPK的有价值的靶标。mTOR-p70 S6激酶信号通路的抑制在二甲双胍对垂体瘤细胞生长的抑制作用中发挥作用。在能量应激条件下，蛋氨酸不影响MIT还原活性。最后，二甲双胍仍然能够诱导AMPK活化，并抑制用毛喉素处理的细胞和过表达GHRH受体并用GHRH处理的转染细胞的细胞生长。因此，腺苷酸环化酶的过度激活并不能解释一些人垂体瘤对AMPK激活化合物缺乏反应的原因。(C)2017爱思唯尔B. V.保留所有权利。
For a few years we have been investigating AMP-activated protein kinase (AMPK) as a target for drug therapy of GH-secreting pituitary adenomas. Aim of this study was to investigate the direct effects of metformin, which causes AMPK activation in different cell types, on rat pituitary adenoma cell growth and on related cell signalling pathways. Our results suggest that metformin can exert a growth-inhibitory activity in rat pituitary tumor cells mediated by AMPK activation, although multiple mechanisms are most likely involved. Membrane proteins, including growth factor receptors, are valuable targets of AMPK. The inhibition of the mTOR-p70S6 kinase signalling pathway plays a role in the suppressive effect of metformin on pituitary tumor cell growth. Metformin did not affect the MIT reduction activity in energetic stress conditions. Finally, metformin was still able to induce AMPK activation and to inhibit cell growth in cells treated with forskolin and in transfected cells overexpressing GHRH-receptor and treated with GHRH. Hence, adenylyl cyclase over-activation does not account for the lack of response of some human pituitary tumors to AMPK-activating compounds in vitro. (C) 2017 Elsevier B.V. All rights reserved.