Abstract
Purpose:
To determine the effect of modulating MAP kinase phosphatase-1 (MKP-1) expression levels on cell death induced by glucocorticoid (GC) or hydroxyurea (HU) treatment in the human pre-B acute lymphoblastic leukemia cell line 697.
Methods:
Stable MKP-1 overexpressing transformants of the 697 pre-B acute lymphoblastic leukemia cell line were created and tested for sensitivity to the GC triamcinolone acetonide (TA) and HU, and compared to a control 697 cell line containing normal MKP-1 expression levels. Small interfering RNAs (siRNAs) were designed to inhibit MKP-1 expression and evaluated for their effect on GC-mediated cell death.
Results:
MKP-1 overexpression caused a phenotype of partial resistance to HU-induced apoptosis but not to GC-induced apoptosis. Electroporation of siRNAs effectively silenced MKP-1 expression, and increased sensitivity to TA by 9.6+/-1.9%.
Conclusions:
Because MKP-1 protects certain tumor cells from chemotherapy-induced apoptosis, its inhibition is being considered as a possible strategy for combination cancer therapy. However, this study suggests that while MKP-1 inhibition may improve the efficacy of DNA damaging agents, it may have only limited utility in combination with glucocorticoids.
Publication types
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Evaluation Study
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Base Sequence
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Caspase 3
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Caspases / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Drug Resistance, Neoplasm
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Dual Specificity Phosphatase 1
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Gene Silencing*
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Glucocorticoids / pharmacology*
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Humans
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Hydroxyurea / pharmacology
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism*
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Immunoblotting
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Molecular Sequence Data
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Protein Phosphatase 1
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Transfection
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Triamcinolone Acetonide / pharmacology*
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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Glucocorticoids
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Immediate-Early Proteins
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RNA, Messenger
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RNA, Small Interfering
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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DUSP1 protein, human
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Dual Specificity Phosphatase 1
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Protein Tyrosine Phosphatases
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CASP3 protein, human
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Caspase 3
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Caspases
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Triamcinolone Acetonide
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Hydroxyurea