Inhibition of Src family kinases enhances retinoic acid–induced gene expression and myeloid differentiation
| Autor: | Robert L. Redner, Michelle B. Miranda, Daniel Johnson |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Acute promyelocytic leukemia
Cancer Research Myeloid Retinoic acid Tretinoin Biology Gene Expression Regulation Enzymologic Cell Line chemistry.chemical_compound Differentiation therapy medicine Humans Enzyme Inhibitors Regulation of gene expression Cluster of differentiation Cell Differentiation Flow Cytometry medicine.disease Molecular biology Retinoic acid receptor src-Family Kinases medicine.anatomical_structure Oncology chemistry Cancer research Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Molecular Cancer Therapeutics. 6:3081-3090 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-07-0514 |
| Popis: | Treatment of acute promyelocytic leukemia with retinoic acid (RA) results in differentiation of the leukemic cells and clinical remission. However, the cellular factors that regulate RA-induced myeloid differentiation are largely unknown, and other forms of acute myelogenous leukemia (AML) do not respond to this differentiation therapy. A greater understanding of the molecules that positively or negatively regulate RA-induced differentiation should facilitate the development of more effective differentiation therapies. In this study, we investigated the potential role of Src family kinases (SFK) in the regulation of RA-induced gene expression and myeloid differentiation. We report that inhibition of SFKs markedly enhanced RA-induced differentiation in myeloid cell lines and primary AML cells, as assessed by flow-cytometric analysis of cell surface markers, morphologic analysis, and nitroblue tetrazolium reduction. In addition, inhibition of SFKs enhanced expression from retinoic acid receptor (RAR) target genes encoding CCAAT/enhancer binding protein ε (C/EBPε), PU.1, intercellular adhesion molecule-1 (ICAM-1), and cathepsin D. Moreover, a constitutively active Src inhibited RAR-dependent transcription, whereas a kinase-dead Src exerted little effect. These studies provide the first demonstration that SFKs act to negatively regulate RA-induced gene expression and myeloid differentiation and suggest that the combination of SFK inhibition and RA treatment may be therapeutically beneficial in AML. [Mol Cancer Ther 2007;6(12):3081–90] |
| Databáze: | OpenAIRE |
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