Src family kinases promote AML cell survival through activation of signal transducers and activators of transcription (STAT).
We investigated the role of Src family kinases (SFKs) in the regulation of STAT activation in myeloid leukemia cells. Two of 6 AML cell lines displayed constitutive STAT5 activation, whereas four cell lines had constitutive SFK activity. Treatment with the SFK inhibitors suppressed STAT5 activation and decreased viability. Akt phosphorylation and Mcl-1 expression decreased after SFK inhibition accompanied by apoptosis induction. In primary AML specimens, SFK inhibitors suppressed proliferation in 5 of 14 specimens. These data indicate that Src-STAT5 and Src-Akt pathways are integral survival signal pathways in AML cells. Src inhibition may represent a novel treatment strategy for investigation in AML.
Ozawa
Yukiyasu
Y
Experimental Therapeutics, H. Lee Moffitt Cancer & Research Institute, Tampa, FL 33612, United States. ozaway@med.nagoya-u.ac.jp
Williams
Ann H
AH
Estes
Myka L
ML
Matsushita
Norimasa
N
Boschelli
Frank
F
Jove
Richard
R
List
Alan F
AF
D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D004791:Enzyme Inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050791:STAT Transcription Factors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt