Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cells
Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cells
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DOI：
10.1016/j.exphem.2015.03.005
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发表时间：
2015-07-01
影响因子：
2.6
通讯作者：
Kirito, Keita
中科院分区：
文献类型：
--
作者：
Kawashima, Ichiro;Mitsumori, Toni;Kirito, Keita
腺苷一磷酸活化蛋白激酶(AMPK)是细胞能量状态的感受器。当细胞能量水平降低时，AMPK被激活，并发挥抑制能量消耗过程的功能，包括蛋白质合成。近年来，AMPK作为一种极具吸引力的肿瘤治疗分子靶点而备受关注。一些研究表明，化学刺激物(如二甲双胍)激活AMPK可诱导多种血液系统恶性肿瘤细胞的凋亡。从另一个角度来看，这些结果表明AMPK的功能在血液肿瘤细胞中受到了损害。然而，这种损伤发生的确切机制还不是很清楚。在黑色素瘤细胞中，致癌的BRAF通过激活细胞外信号调节激酶(ERK)途径，使5‘-腺苷一磷酸活化蛋白激酶(AMPK)的上游激活物--肝激酶B1磷酸化，导致肝激酶B1和AMPK失活。在这项研究中，我们利用已建立的和原代的人类白血病细胞分析了ERK是否参与了AMPK活性的抑制。我们发现，在去糖或二甲双胍刺激下，ERK的活性强度与AMPK的激活程度呈负相关。我们还发现，U0126对ERK活性的抑制可使二甲双胍处理后的AMPK活性恢复。此外，二甲双胍和U0126的联合治疗增强了二甲双胍的抗白血病活性。重要的是，二甲双胍通过抑制ERK的负性调节因子双特异性磷酸酶6的蛋白水平来诱导ERK的激活。AMPK和ERK之间的这种串扰可能会降低二甲双胍的抗白血病活性。综上所述，我们目前的观察结果提示了一种新的治疗策略，以提高二甲双胍治疗白血病的疗效。版权所有(C)2015 ISEH-国际实验血液学学会。由爱思唯尔公司出版。
Adenosine monophosphate activated protein kinase (AMPK) is a sensor for cellular energy status. When the cellular energy level is decreased, AMPK is activated and functions to suppress energy-consuming processes, including protein synthesis. Recently, AMPK has received attention as an attractive molecular target for cancer therapy. Several studies have revealed that the activation of AMPK by chemical stimulators, such as metformin, induces apoptosis in a variety of hematologic malignant cells. From another perspective, these results suggest that the function of AMPK is impaired in hematologic tumor cells. However, the precise mechanisms by which this impairment occurs are not well understood. In melanoma cells, oncogenic BRAF constitutively activates the extracellular signal-regulated kinase (ERK) pathway and phosphorylates liver kinase B1, an upstream activator of 5' adenosine monophosphate activated protein kinase (AMPK), resulting in the inactivation of liver kinase B1 and AMPK. In this study, we analyzed whether ERK is involved in the suppression of AMPK activity using established and primary human leukemia cells. We found an inverse correlation between the intensity of ERK activity and the degree of AMPK activation after stimulation with either glucose deprivation or metformin. We also found that the inhibition of ERK activity by U0126 restored AMPK activation after metformin treatment. Furthermore, a combined treatment with metformin and U0126 enhanced the antileukemic activity of metformin. Importantly, metformin induced ERK activation by suppressing the protein levels of dual specificity phosphatase 6, a negative regulator of ERK. This crosstalk between AMPK and ERK could diminish the antileukemic activity of metformin. Taken together, our present observations suggest a novel therapeutic strategy for improving the efficacy of metformin in treating leukemia. Copyright (C) 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.