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Abstract
Imatinib mesylate, the inhibitor of the KIT protein tyrosine kinase that is constitutively activated in Gastrointestinal Stromal Tumors (GISTs), has been established as the first highly effective drug in the treatment of patients with advanced GISTs. Recent studies suggest that changes in the glucose metabolism could be an additional mechanism of the anti-proliferative action of imatinib. The aim of this study was to investigate the effect on glucose flux and metabolism in a human GIST882 cell line after exposure to imatinib. Imatinib induced a concentration-dependent inhibition of cell proliferation in GIST882 cells (IC50, 0.030 ± 0.006 μM). By 18F-FDG uptake measurements, after 24 h exposure to the drug at concentrations of 0.03 μM and 0.3 μM, the glucose uptake decreased by ~25% and ~95%, respectively. Moreover, after a 3-h treatment at the concentration of 0.3 μM of imatinib the decrease in glucose-uptake was already more than 50%. After 24-h of treatment with 0.3 μM imatinib, the measurements of the hexokinase and glucose-6-phosphate dehydrogenase activity revealed a 30% and 37% decrease, respectively. Western blotting disclosed mainly expression of glucose transporter GLUT-2 in GIST cells. Exposure of GIST cells to imatinib resulted in the decline of the GLUT-2 receptor recruitment to cell membrane, which paralleled with the elevated amount of the total KIT protein. These findings suggest that a rapid decline in glucose uptake following imatinib treatment in GIST cells is dependent on glucose transporter impaired anchorage to the plasma membrane, with the subsequent recruitment of KIT protein.
Highlights
The antineoplastic drug imatinib mesylate, a derivative of 2-phenylaminopyrimidine, known as Glivec, Gleevec or STI-571, was initially developed as a competitive inhibitor of BCR-ABL, a fusion protein and constitutively active protein tyrosine kinase that was identified as the primary cause of Philadelphia chromosome positive Chronic Myelogenous Leukemia (CML)[1]
As a comparison we evaluated the presence of GLUT transporters in an imatinib resistant cell line Gastrointestinal Stromal Tumors (GISTs) GDG1 and found the presence of GLUT-2 and GLUT-4 and GLUT-3, which could signify that GIST cells can express different glucose-transporters depending on their glucose requirements
Its impaired recruitment to the plasma membrane combined with the decreased hexokinase activity may account for the rapid decline in glucose utilization shortly after imatinib treatment
Summary
The antineoplastic drug imatinib mesylate, a derivative of 2-phenylaminopyrimidine, known as Glivec , Gleevec or STI-571, was initially developed as a competitive inhibitor of BCR-ABL, a fusion protein and constitutively active protein tyrosine kinase that was identified as the primary cause of Philadelphia chromosome positive Chronic Myelogenous Leukemia (CML)[1]. GISTs are the most common mesenchymal tumors in the gastrointestinal tract These tumors are characterized by the ubiquitous expression of the protein tyrosine kinase KIT, the receptor for Stem Cell Factor (SCF)[6,7,8]. The majority of GISTs harbor KIT somatic gain-of function mutations, most commonly in the highly conserved juxtamembrane region encoded by exon 11. These mutations are associated with a constitutive activation of the receptor, which promotes proliferation and anti-apoptotic signaling in the absence of the ligand[10,11,12,13]
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