Abstract
Glucocorticoids are used as part of front-line therapy to treat lymphoid malignancy because of their remarkable ability to induce apoptosis. Yet, in T cells, glucocorticoid-induced apoptosis is readily inhibited by lymphocyte activation and signaling. We have previously shown that the Src family kinase, Lck (lymphocyte cell-specific tyrosine kinase), which is predominantly expressed in T cells, interacts with IP3 receptors to facilitate calcium signaling. Here, we discovered that dexamethasone downregulates Lck, which, in turn, suppresses lymphocyte activation by inhibiting pro-survival calcium oscillations. Moreover, stable expression of shRNAs that selectively targeted Lck or treatment with the Src inhibitor dasatinib (BMS-354825) enhanced apoptosis induction by dexamethasone. To investigate the effect of Lck inhibition in a primary leukemia model, we employed chronic lymphocytic leukemia (CLL) cells that aberrantly expressed Lck and were relatively insensitive to dexamethasone. Lck expression was correlated with resistance to dexamethasone in CLL cells, and its inhibition by dasatinib or other inhibitors markedly enhanced glucocorticoid sensitivity. Collectively, these data indicate that Lck protects cells from glucocorticoid-induced apoptosis and its inhibition enhances sensitivity to dexamethasone. Small-molecule inhibitors of Lck, such as dasatinib, may function to reverse glucocorticoid resistance in some lymphoid malignancies.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis / drug effects*
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Apoptosis / immunology
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B-Lymphocytes / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / immunology
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Cell Line, Tumor
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Cells, Cultured
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Dasatinib
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Dexamethasone / pharmacology
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Down-Regulation / genetics
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Drug Resistance, Neoplasm / drug effects*
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Drug Synergism
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Gene Expression Profiling
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Glucocorticoids / pharmacology*
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Lymphocyte Activation / drug effects
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
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Lymphocytes / cytology*
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Lymphocytes / drug effects*
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Lymphocytes / immunology
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Mice
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Mice, Inbred Strains
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Pyrimidines / pharmacology
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RNA, Small Interfering / genetics
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Receptors, Antigen, T-Cell / agonists
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Signal Transduction / drug effects
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Signal Transduction / immunology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Thiazoles / pharmacology
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Tumor Cells, Cultured
Substances
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Glucocorticoids
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Protein Kinase Inhibitors
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Pyrimidines
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RNA, Small Interfering
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Receptors, Antigen, T-Cell
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Thiazoles
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Dexamethasone
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Dasatinib