Imatinib Mesylate Inhibits Glucose Uptake in Gastrointestinal Stromal Tumor Cells by Downregulation of the Glucose Transporters Recruitment to the Plasma Membrane
Hans Prenen, Cristiana Stefan, Bart Landuyt, Peter Vermaelen, Maria Debiec-Rychter, Mathieu Bollen, Sigrid Stroobants, Ernst de Bruijn, Luc Mortelmans, Raf Sciot, Patrick Schöffski and Allan van Oosterom
DOI : 10.3844/ajbbsp.2005.95.102
American Journal of Biochemistry and Biotechnology
Volume 1, Issue 2
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.
© 2005 Hans Prenen, Cristiana Stefan, Bart Landuyt, Peter Vermaelen, Maria Debiec-Rychter, Mathieu Bollen, Sigrid Stroobants, Ernst de Bruijn, Luc Mortelmans, Raf Sciot, Patrick Schöffski and Allan van Oosterom. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.