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Abnormalities in glucose uptake and metabolism in imatinib-resistant human BCR-ABL positive cells

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dc.contributor.authorKominsky, D.
dc.contributor.authorKlawitter, J.
dc.contributor.authorBrown, J.
dc.contributor.authorBoros, L.
dc.contributor.authorVaz de Melo, J.
dc.contributor.authorEckhardt, S.
dc.contributor.authorSerkova, N.
dc.date.issued2009
dc.description.abstractThe 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.
dc.description.statementofresponsibilityDouglas J. Kominsky, Jaimi L. Brown, Laszlo G. Boros, Junia V. Melo, S. Gail Eckhardt and Natalie J. Serkova
dc.identifier.citationClinical Cancer Research, 2009; 15(10):3442-3450
dc.identifier.doi10.1158/1078-0432.CCR-08-3291
dc.identifier.issn1078-0432
dc.identifier.issn1557-3265
dc.identifier.orcidVaz de Melo, J. [0009-0009-5343-4893]
dc.identifier.urihttp://hdl.handle.net/2440/58658
dc.language.isoen
dc.publisherAmer Assoc Cancer Research
dc.rightsCopyright 2009 American Association for Cancer Research.
dc.source.urihttps://doi.org/10.1158/1078-0432.ccr-08-3291
dc.subjectCell Line, Tumor
dc.subjectK562 Cells
dc.subjectHumans
dc.subjectCarbon Isotopes
dc.subjectBenzamides
dc.subjectPiperazines
dc.subjectPyrimidines
dc.subjectDeoxyglucose
dc.subjectGlucose
dc.subjectRibose
dc.subjectRNA, Neoplasm
dc.subjectAntineoplastic Agents
dc.subjectBlotting, Western
dc.subjectMagnetic Resonance Spectroscopy
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectProtein Transport
dc.subjectDrug Resistance, Neoplasm
dc.subjectTime Factors
dc.subjectGlucose Transporter Type 1
dc.subjectGas Chromatography-Mass Spectrometry
dc.subjectLeukemia, Myelogenous, Chronic, BCR-ABL Positive
dc.subjectImatinib Mesylate
dc.titleAbnormalities in glucose uptake and metabolism in imatinib-resistant human BCR-ABL positive cells
dc.typeJournal article
pubs.publication-statusPublished

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