Activation of adenosine monophosphate activated protein kinase inhibits growth of multiple myeloma cells
Activation of adenosine monophosphate activated protein kinase inhibits growth of multiple myeloma cells
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DOI：
10.1016/j.yexcr.2007.06.020
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发表时间：
2007-10-01
影响因子：
3.7
通讯作者：
Schmidmaier, Ralf
中科院分区：
文献类型：
--
作者：
Baumann, Philipp;Mandl-Weber, Sonja;Schmidmaier, Ralf
单磷酸腺苷活化蛋白激酶（AMPK）在调节多发性骨髓瘤（MM）细胞生长中的作用尚不清楚。在本研究中，我们发现AMPK激活剂5-氨基咪唑-4-羧酰胺核苷（AICAr）和D942抑制MM细胞株的细胞生长。AICAr还在所有四种测试细胞系中诱导s期细胞周期阻滞，并导致AMPK磷酸化从而激活。此外，硝基苄基硫代9- β - d -核糖呋喃嘧啶嘌呤（NBTI）对核苷转运体的抑制、碘结核菌嘧啶对腺苷激酶的抑制以及AMPKI化合物C对AMPK的抑制逆转了AICAr的作用，表明AICAr的细胞效应是由AMPK介导的。AMPK的激活抑制了基底细胞外信号调节激酶（ERK）、哺乳动物雷帕霉素靶蛋白（mTOR）和P70S6激酶（P70S6K）以及AKT的磷酸化，并阻断了11-6、IGF-1和HS-5基质细胞条件培养基诱导的细胞生长增加。先前已被证明可以激活AMPK的曲格列酮，同样可以抑制MM细胞生长，激活AMPK，并降低ERK和P70S6K的磷酸化。我们的研究结果表明，AMPK的激活可以抑制MM细胞的生长，尽管有IL-6、IGF-1或HS-5基质细胞条件培养基的刺激，这代表了MM治疗的潜在新靶点。版权所有。
The role of adenosine monophosphate activated protein kinase (AMPK) in regulating multiple myeloma (MM) cell growth is not yet clear. in this study, we show that the AMPK activators 5-aminoimidazole-4-carboxamide riboside (AICAr) and D942 inhibit cell growth in MM cell lines. AICAr also induced an S-phase cell cycle arrest in all four tested cell lines and led to phosphorylation and thus activation of AMPK. Furthermore, the inhibition of a nucleoside transporter by nitrobenzyl-thio-9-beta-D-ribofuranosylpurine (NBTI), inhibition of the adenosine kinase by iodotubericidine and inhibition of AMPK by AMPKI Compound C reversed AICAr effects, indicating that the cellular effects of AICAr were mediated by AMPK. Activation of AMPK inhibited basal extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR) and P70S6 kinase (P70S6K) as well as AKT phosphorylation, and blocked 11-6, IGF-1, and HS-5 stromal cell conditioned medium-induced increase of cell growth. Troglitazone, which has previously been shown to activate AMPK, similarly inhibited MM cell growth, activated AMPK, and decreased ERK and P70S6K phosphorylation. our results suggest that activation of AMPK inhibits MM cell growth despite stimulation with IL-6, IGF-1, or HS-5 stromal cell conditioned medium and represents a potential new target in the therapy of MM. (c) 2007 Elsevier Inc. All rights reserved.