In BCR-ABL-positive cells, STAT-5 tyrosine-phosphorylation integrates signals induced by imatinib mesylate and Ara-C.
In BCR-ABL-positive cells, the transcription factor STAT-5 is constitutively activated by tyrosine phosphorylation. STAT-5 activation results in upregulation of bcl-X(L) and increased resistance to induction of apoptosis. Here, we investigated the effects of imatinib mesylate and cytosine arabinoside (Ara-C) on STAT-5 tyrosine-phosphorylation, cellular proliferation and induction of apoptosis in cell lines and primary hematopoietic cells. Imatinib mesylate treatment strongly suppressed STAT-5 tyrosine-phosphorylation in K562 and primary CML blasts. In contrast to JAK-2 and PI-3-kinase inhibition, exposure of K562 cells to imatinib mesylate resulted in obvious suppression of proliferation. Reduced cell growth was due to specific induction of caspase activation followed by apoptotic cell death. In addition, we investigated the effects of Ara-C on STAT-5 tyrosine-phosphorylation. Exposure to Ara-C resulted in significant downregulation of STAT-5 tyrosine-phosphorylation and inhibition of DNA binding. Treatment of K562 cells with Ara-C in combination with imatinib mesylate revealed synergistic effects at the level of STAT-5 tyrosine-phosphorylation and DNA binding, Hck tyrosine-phosphorylation, cell growth and induction of apoptosis. Overall, in this report we demonstrate that STAT-5 tyrosine-phosphorylation is a specific target of imatinib mesylate and Ara-C. Our results suggest that, in combination therapy, inhibition of STAT-5 tyrosine-phosphorylation may be responsible for synergistic or additive effects on BCR-ABL-positive cells.
Kindler
T
T
III Medical Department (Hematology/Oncology), Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, Mainz 55101, Germany.
Breitenbuecher
F
F
Kasper
S
S
Stevens
T
T
Carius
B
B
Gschaidmeier
H
H
Huber
C
C
Fischer
T
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D020287:In Situ Nick-End Labeling; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology; D008894:Milk Proteins; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D020298:U937 Cells
D000970:Antineoplastic Agents; D001549:Benzamides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008894:Milk Proteins; D010879:Piperazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D003561:Cytarabine; D014443:Tyrosine; D000068877:Imatinib Mesylate; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D020169:Caspases