Department of Oncology, McGill University, Montreal, Quebec, Canada.
PLoS One. 2012;7(11):e49513. doi: 10.1371/journal.pone.0049513. Epub 2012 Nov 21.
KU-55933 is a specific inhibitor of the kinase activity of the protein encoded by Ataxia telangiectasia mutated (ATM), an important tumor suppressor gene with key roles in DNA repair. Unexpectedly for an inhibitor of a tumor suppressor gene, KU-55933 reduces proliferation. In view of prior preliminary evidence suggesting defective mitochondrial function in cells of patients with Ataxia Telangiectasia (AT), we examined energy metabolism of cells treated with KU-55933. The compound increased AMPK activation, glucose uptake and lactate production while reducing mitochondrial membrane potential and coupled respiration. The stimulation of glycolysis by KU-55933 did not fully compensate for the reduction in mitochondrial functions, leading to decreased cellular ATP levels and energy stress. These actions are similar to those previously described for the biguanide metformin, a partial inhibitor of respiratory complex I. Both compounds decreased mitochondrial coupled respiration and reduced cellular concentrations of fumarate, malate, citrate, and alpha-ketogluterate. Succinate levels were increased by KU-55933 levels and decreased by metformin, indicating that the effects of ATM inhibition and metformin are not identical. These observations suggest a role for ATM in mitochondrial function and show that both KU-55933 and metformin perturb the TCA cycle as well as oxidative phosphorylation.
KU-55933 是共济失调毛细血管扩张突变蛋白（ATM）激酶活性的特异性抑制剂，ATM 是一个重要的肿瘤抑制基因，在 DNA 修复中起关键作用。令人意外的是，作为肿瘤抑制基因抑制剂的 KU-55933 会降低细胞增殖。鉴于先前有初步证据表明，共济失调毛细血管扩张症（AT）患者的细胞中线粒体功能有缺陷，我们检查了用 KU-55933 处理的细胞的能量代谢。该化合物增加了 AMPK 的激活、葡萄糖摄取和乳酸生成，同时降低了线粒体膜电位和偶联呼吸。KU-55933 对糖酵解的刺激并不能完全补偿线粒体功能的降低，导致细胞内 ATP 水平降低和能量应激。这些作用与先前描述的二甲双胍类似，二甲双胍是呼吸复合物 I 的部分抑制剂。这两种化合物都降低了线粒体偶联呼吸，并降低了细胞中富马酸、苹果酸、柠檬酸和α-酮戊二酸的浓度。KU-55933 增加了琥珀酸的水平，而二甲双胍降低了琥珀酸的水平，表明 ATM 抑制和二甲双胍的作用并不完全相同。这些观察结果表明 ATM 在线粒体功能中的作用，并表明 KU-55933 和二甲双胍都干扰了 TCA 循环和氧化磷酸化。
