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Chronic myeloid leukaemia: an investigation into the role of Bcr-Abl-induced abnormalities in glucose transport regulation.
- Source :
-
Oncogene [Oncogene] 2005 May 05; Vol. 24 (20), pp. 3257-67. - Publication Year :
- 2005
-
Abstract
- In chronic myeloid leukaemia (CML) expression of the chimeric tyrosine kinase, Bcr-Abl, promotes the inappropriate survival of haemopoietic stem cells by a nonautocrine mechanism in the absence of IL-3. Stimulation of glucose uptake appears to play an important role in the suppression of apoptosis by this cytokine in normal haemopoietic cells. To investigate whether the cell survival mechanisms mediated by the oncoprotein and cytokine showed any similarities, we employed a haemopoietic cell line, TonB210, engineered for inducible expression of Bcr-Abl. Tyrosine kinase expression in cytokine-deprived cells was found to mimic the effect of IL-3 in maintaining a higher V(max) for hexose uptake. In both IL-3- treated cells and those expressing Bcr-Abl, high rates of hexose uptake were associated with the retention at the cell surface of approximately 80% of the total cellular content of the GLUT1 glucose transporter. In contrast, treatment of Bcr-Abl-expressing cells for 6 h with the Bcr-Abl kinase inhibitor Glivec (10 muM), in the absence of IL-3, led to internalization of approximately 90% of the cell-surface transporters and drastically decreased (4.4+/-0.9 (mean+/-s.e.m., 4)-fold) the V(max) for hexose uptake, without significant effect on the K(m) for this process or on the total cellular transporter content. These effects were not the result of any significant loss in cell viability, and preceded the onset of apoptosis caused by inhibition of Bcr-Abl. Both IL-3 treatment and expression of Bcr-Abl led to enhanced phosphorylation of Akt (protein kinase B). The stimulation of transport by IL-3 and Bcr-Abl in TonB210 cells was inhibitable by phosphatidylinositol 3-kinase inhibitors, indicating the involvement of this kinase in the signal transduction pathway. These findings suggest that inhibition of glucose transport plays an important role in the therapeutic action of Glivec, and that the signal transduction pathways involved in transport stimulation by Bcr-Abl may offer novel therapeutic targets for CML.
- Subjects :
- Annexin A5 pharmacology
Apoptosis
Benzamides
Biological Transport
Blotting, Western
Cell Survival
Cytokines metabolism
Deoxyglucose metabolism
Dose-Response Relationship, Drug
Doxycycline pharmacology
Enzyme Inhibitors pharmacology
Flow Cytometry
Glucose Transporter Type 1
Hematopoietic Stem Cells metabolism
Humans
Imatinib Mesylate
Immunohistochemistry
Interleukin-3 metabolism
Kinetics
Monosaccharide Transport Proteins metabolism
Phosphatidylinositol 3-Kinases metabolism
Phosphorylation
Piperazines pharmacology
Protein Serine-Threonine Kinases metabolism
Protein-Tyrosine Kinases metabolism
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-akt
Pyrimidines pharmacology
Temperature
Time Factors
Fusion Proteins, bcr-abl metabolism
Glucose metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 24
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 15735728
- Full Text :
- https://doi.org/10.1038/sj.onc.1208461