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|Title:||Abnormalities in glucose uptake and metabolism in imatinib-resistant human BCR-ABL positive cells|
Vaz de Melo, J.
|Citation:||Clinical Cancer Research, 2009; 15(10):3442-3450|
|Publisher:||Amer Assoc Cancer Research|
|Douglas J. Kominsky, Jaimi L. Brown, Laszlo G. Boros, Junia V. Melo, S. Gail Eckhardt and Natalie J. Serkova|
|Abstract:||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 antiproliferative 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 13C 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 13C-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.|
|Keywords:||Cell Line, Tumor; K562 Cells; Humans; Carbon Isotopes; Piperazines; Pyrimidines; Deoxyglucose; Glucose; Ribose; RNA, Neoplasm; Antineoplastic Agents; Blotting, Western; Magnetic Resonance Spectroscopy; Reverse Transcriptase Polymerase Chain Reaction; Protein Transport; Drug Resistance, Neoplasm; Time Factors; Glucose Transporter Type 1; Gas Chromatography-Mass Spectrometry; Leukemia, Myelogenous, Chronic, BCR-ABL Positive|
|Rights:||Copyright 2009 American Association for Cancer Research.|
|Appears in Collections:||Medicine publications|
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