AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow.
AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow.
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DOI：
10.1016/j.stem.2015.08.019
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发表时间：
2015-11-05
期刊：
影响因子：
23.9
通讯作者：
Nakada D
中科院分区：
文献类型：
--
作者：
Saito Y;Chapple RH;Lin A;Kitano A;Nakada D
癌细胞如何适应患者的代谢不良条件并努力增殖是癌症生物学中的一个基本问题。在这里，我们展示了AMP激活的蛋白激酶(AMPK)，一种代谢检查点激酶，赋予白血病启动细胞(LICs)代谢应激抵抗，并促进白血病的发生。在饮食限制时，MLL-AF9诱导的小鼠AML激活AMPK并维持白血病潜能。AMPK缺失通过减少葡萄糖转运蛋白1(Glut1)的表达，降低葡萄糖流量，增加氧化应激和DNA损伤，显著延迟白血病的发生和耗尽LICs。在低血糖的骨髓环境中，LICs尤其依赖AMPK来抑制氧化应激。值得注意的是，AMPK抑制与饮食限制引起的生理性代谢应激有协同作用，并深刻抑制了白血病的发生。我们的结果表明，AMPK保护LIC免受代谢应激的影响，AMPK抑制和生理性代谢应激结合可通过诱导氧化应激和DNA损伤来有效地抑制AML。
How cancer cells adapt to metabolically adverse conditions in patients and strive to proliferate is a fundamental question in cancer biology. Here we show that AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase, confers metabolic stress resistance to leukemia-initiating cells (LICs) and promotes leukemogenesis. Upon dietary restriction, MLL-AF9-induced murine AML activated AMPK and maintained leukemogenic potential. AMPK deletion significantly delayed leukemogenesis and depleted LICs by reducing the expression of glucose transporter 1 (Glut1), compromising glucose flux, and increasing oxidative stress and DNA damage. LICs were particularly dependent on AMPK to suppress oxidative stress in the hypoglycemic bone marrow environment. Strikingly, AMPK inhibition synergized with physiological metabolic stress caused by dietary restriction and profoundly suppressed leukemogenesis. Our results indicate that AMPK protects LICs from metabolic stress, and that combining AMPK inhibition with physiological metabolic stress potently suppresses AML by inducing oxidative stress and DNA damage.