Evaluation of glucocorticoid sensitivity in 697 pre-B acute lymphoblastic leukemia cells after overexpression or silencing of MAP kinase phosphatase-1

• Published in: Journal of cancer research and clinical oncology Vol. 131; no. 6; pp. 347 - 354
• Main Authors: ABRAMS, Marc T, ROBERTSON, Noreen M, LITWACK, Gerald, WICKSTROM, Eric
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.06.2005; Springer Nature B.V
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Base Sequence; Biological and medical sciences; Caspase 3; Caspases - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chemotherapy; Deoxyribonucleic acid; DNA; Drug Resistance, Neoplasm; Dual Specificity Phosphatase 1; Gene Silencing; Genotype & phenotype; Glucocorticoids - pharmacology; Hematologic and hematopoietic diseases; Humans; Hydroxyurea - pharmacology; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Immunoblotting; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Molecular Sequence Data; Oncology; Pharmacology. Drug treatments; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Protein Phosphatase 1; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Proteins; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; Transfection; Triamcinolone Acetonide - pharmacology; Antineoplastic agent; ALL; RNA interference; Phosphoric monoester hydrolases; Gene overexpression; Esterases; Glucocorticoid; Lymphoproliferative syndrome; Acute lymphocytic leukemia; Evaluation; Enzyme; Acute; Precursor cell; Mitogen-activated protein kinase; Small Interference RNA; Malignant hemopathy; B-Lymphocyte; siRNA; In vitro; Gene silencing; Sensitivity resistance; Cell death; MKP-1; Hydrolases; Apoptosis
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-004-0659-3

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. 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. 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%. 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.