Document Detail

JS-K, a nitric oxide-releasing prodrug, modulates ß-catenin/TCF signaling in leukemic Jurkat cells: evidence of an S-nitrosylated mechanism.
MedLine Citation:
PMID:  20797387     Owner:  NLM     Status:  MEDLINE    
β-Catenin is a central player of the Wnt signaling pathway that regulates cell-cell adhesion and may promote leukemia cell proliferation. We examined whether JS-K, an NO-donating prodrug, modulates the Wnt/β-catenin/TCF-4 signaling pathway in Jurkat T-Acute Lymphoblastic Leukemia cells. JS-K inhibited Jurkat T cell growth in a concentration and time-dependent manner. The IC(50)s for cell growth inhibition were 14±0.7 and 9±1.2μM at 24 and 48h, respectively. Treatment of the cells with JS-K for 24h, caused a dose-dependent increase in apoptosis from 16±3.3% at 10μM to 74.8±2% at 100μM and a decrease in proliferation. This growth inhibition was also due, in part, to alterations in the different phases of the cell cycle. JS-K exhibited a dose-dependent cytotoxicity as measured by LDH release at 24h. However, between 2 and 8h, LDH release was less than 20% for any indicated JS-K concentration. The β-catenin/TCF-4 transcriptional inhibitory activity was reduced by 32±8, 63±5, and 93±2% at 2, 10, and 25μM JS-K, respectively, based on luciferase reporter assays. JS-K reduced nuclear β-catenin and cyclin D1 protein levels, but cytosolic β-catenin expression did not change. Based on a time-course assay of S-nitrosylation of proteins by a biotin switch assay, S-nitrsolyation of nuclear β-catenin was determined to precede its degradation. A comparison of the S-nitrosylated nuclear β-catenin to the total nuclear β-catenin showed that β-catenin protein levels were degraded at 24h, while S-nitrosylation of β-catenin occurred earlier at 0-6h. The NO scavenger PTIO abrogated the JS-K mediated degradation of β-catenin demonstrating the need for NO.
Niharika Nath; Mitali Chattopadhyay; Liliya Pospishil; Lucyna Z Cieciura; Satindra Goswami; Ravinder Kodela; Joseph E Saavedra; Larry K Keefer; Khosrow Kashfi
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2010-08-24
Journal Detail:
Title:  Biochemical pharmacology     Volume:  80     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-10-18     Completed Date:  2010-11-05     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1641-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Department of Physiology and Pharmacology, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY 10031, United States.
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MeSH Terms
Apoptosis / drug effects,  physiology
Azo Compounds / pharmacology*
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology*
Growth Inhibitors / pharmacology
Jurkat Cells
Nitric Oxide / physiology,  secretion*
Nitroso Compounds / pharmacology
Piperazines / pharmacology*
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy,  metabolism*,  pathology
Prodrugs / pharmacology*
Signal Transduction / drug effects,  physiology*
Transcription Factors / physiology*
Wnt Proteins / physiology
beta Catenin / physiology*
Reg. No./Substance:
0/Azo Compounds; 0/Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; 0/Growth Inhibitors; 0/Nitroso Compounds; 0/O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate; 0/Piperazines; 0/Prodrugs; 0/TCF4 protein, human; 0/Transcription Factors; 0/Wnt Proteins; 0/beta Catenin; 10102-43-9/Nitric Oxide

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