Abnormalities in Glucose Uptake and Metabolism in Imatinib-Resistant Human BCR-ABL-Positive Cells
Abnormalities in Glucose Uptake and Metabolism in Imatinib-Resistant Human BCR-ABL-Positive Cells
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DOI：
10.1158/1078-0432.ccr-08-3291
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发表时间：
2009-05-15
影响因子：
11.5
通讯作者：
Serkova, Natalie J.
中科院分区：
文献类型：
--
作者：
Kominsky, Douglas J.;Klawitter, Jelena;Serkova, Natalie J.
伊马替尼耐药性的发展已成为一个重要的治疗问题，其病因似乎是多因素的，而且知之甚少。截至目前，除骨髓增殖反弹外，预测慢性粒细胞白血病(CML)患者对伊马替尼耐药的临床标准正在制定中。然而，有证据表明，控制葡萄糖-底物流量是伊马替尼抗增殖作用的重要机制，因为伊马替尼耐药的胃肠道间质KIT阳性肿瘤在放射学图像中表现出高度的葡萄糖摄取。我们利用核磁共振波谱和气相色谱-质谱仪分析了伊马替尼作用于对伊马替尼敏感性不同的CML细胞系过程中C-13葡萄糖的摄取和代谢(糖酵解、TCA循环和核酸核糖合成)。我们的结果表明，敏感的K562-S和LAMA84-S bcr-abl阳性细胞在伊马替尼处理后，葡萄糖摄取减少，乳酸产生减少，氧化三氯乙酸循环得到改善。耐药的K562-r和LAMA84-r细胞保持高度糖酵解代谢表型，葡萄糖摄取和乳酸产生增加。此外，在伊马替尼耐药细胞中，通过葡萄糖-6-磷酸脱氢酶从C-13-葡萄糖氧化合成RNA核糖减少，通过非氧化转酮醇酶途径合成RNA增加。CML细胞对伊马替尼敏感，其核糖合成的(氧化/非氧化)流量比为-GT；1。抗性株K562-r和LAMA84-r的氧化/非氧化通量比为0.7。在伊马替尼处理的敏感细胞中，葡萄糖摄取和代谢的改变伴随着GLUT-1从质膜向细胞内的移位，而在LAMA84-r和K562-r细胞中，GLUT-1仍然定位在质膜上。GLUT-1的总蛋白负载量在处理的敏感和耐药细胞系中没有变化。综上所述，葡萄糖摄取增加和非氧化糖酵解代谢表型可作为早期检测bcr-abl阳性细胞中伊马替尼耐药的敏感指标。
The development of imatinib resistance has become a significant therapeutic problem in which the etiology seems to be multifactorial and poorly understood. As of today, clinical criteria to predict the development of imatinib resistance in chronic myelogenous leukemia (CML), other than rebound of the myeloproliferation, are under development. However, there is evidence that the control of glucose-substrate flux is an important mechanism of the anti proliferative action of imatinib because imatinib-resistant gastrointestinal stromal KIT-positive tumors reveal highly elevated glucose uptake in radiologic images. We used nuclear magnetic resonance spectroscopy and gas chromatography mass spectrometry to assess C-13 glucose uptake and metabolism (glycolysis, TCA cycle, and nucleic acid ribose synthesis) during imatinib treatment in CML cell lines with different sensitivities to imatinib. Our results show that sensitive K562-s and LAMA84-s BCR-ABL-positive cells have decreased glucose uptake, decreased lactate production, and an improved oxidative TCA cycle following imatinib treatment. The resistant K562-r and LAMA84-r cells maintained a highly glycolytic metabolic phenotype with elevated glucose uptake and lactate production. In addition, oxidative synthesis of RNA ribose from C-13-glucose via glucose-6-phosphate dehydrogenase was decreased, and RNA synthesis via the nonoxidative transketolase pathway was increased in imatinib-resistant cells. CML cells which exhibited a (oxidative/nonoxidative) flux ratio for nucleic acid ribose synthesis of > 1 were sensitive to imatinib. The resistant K562-r and LAMA84-r exhibited a (oxidative/nonoxidative) flux ratio of < 0.7. The changes in glucose uptake and metabolism were accompanied by intracellular translocation of GLUT-1 from the plasma membrane into the intracellular fraction in sensitive cells treated with imatinib, whereas GLUT-1 remained located at the plasma membrane in LAMA84-r and K562-r cells. The total protein load of GLUT-1 was unchanged among treated sensitive and resistant cell lines. In summary, elevated glucose uptake and nonoxidative glycolytic metabolic phenotype can be used as sensitive markers for early detection of imatinib resistance in BCR-ABL-positive cells.