Equipe 4 UMR 837 Inserm, Faculté de Médecine, Université de Lille II, Lille, France.
PLoS One. 2011;6(7):e21924. doi: 10.1371/journal.pone.0021924. Epub 2011 Jul 18.
Challenges today concern chronic myeloid leukemia (CML) patients resistant to imatinib. There is growing evidence that imatinib-resistant leukemic cells present abnormal glucose metabolism but the impact on mitochondria has been neglected. Our work aimed to better understand and exploit the metabolic alterations of imatinib-resistant leukemic cells. Imatinib-resistant cells presented high glycolysis as compared to sensitive cells. Consistently, expression of key glycolytic enzymes, at least partly mediated by HIF-1α, was modified in imatinib-resistant cells suggesting that imatinib-resistant cells uncouple glycolytic flux from pyruvate oxidation. Interestingly, mitochondria of imatinib-resistant cells exhibited accumulation of TCA cycle intermediates, increased NADH and low oxygen consumption. These mitochondrial alterations due to the partial failure of ETC were further confirmed in leukemic cells isolated from some imatinib-resistant CML patients. As a consequence, mitochondria generated more ROS than those of imatinib-sensitive cells. This, in turn, resulted in increased death of imatinib-resistant leukemic cells following in vitro or in vivo treatment with the pro-oxidants, PEITC and Trisenox, in a syngeneic mouse tumor model. Conversely, inhibition of glycolysis caused derepression of respiration leading to lower cellular ROS. In conclusion, these findings indicate that imatinib-resistant leukemic cells have an unexpected mitochondrial dysfunction that could be exploited for selective therapeutic intervention.
今天的挑战涉及对伊马替尼耐药的慢性髓性白血病（CML）患者。越来越多的证据表明，对伊马替尼耐药的白血病细胞存在异常的葡萄糖代谢，但对线粒体的影响却被忽视了。我们的工作旨在更好地理解和利用伊马替尼耐药白血病细胞的代谢改变。与敏感细胞相比，伊马替尼耐药细胞表现出更高的糖酵解活性。一致地，关键糖酵解酶的表达，至少部分由 HIF-1α 介导，在伊马替尼耐药细胞中发生改变，表明伊马替尼耐药细胞将糖酵解通量与丙酮酸氧化解偶联。有趣的是，伊马替尼耐药细胞的线粒体积累了 TCA 循环中间产物，增加了 NADH 和低耗氧量。这些由于 ETC 部分失效导致的线粒体改变在一些伊马替尼耐药 CML 患者分离的白血病细胞中得到了进一步证实。因此，线粒体产生的 ROS 比伊马替尼敏感细胞多。反过来，这导致在同基因小鼠肿瘤模型中，用促氧化剂 PEITC 和 Trisenox 进行体外或体内治疗后，伊马替尼耐药白血病细胞的死亡增加。相反，抑制糖酵解会导致呼吸解抑制，从而降低细胞内的 ROS。总之，这些发现表明，伊马替尼耐药白血病细胞存在意想不到的线粒体功能障碍，这可能被用于选择性的治疗干预。
