Abstract
Dual specificity protein phosphatase 26 (DUSP26) is overexpressed in high-risk neuroblastoma (NB) and contributes to chemoresistance by inhibiting p53 function. In vitro, DUSP26 has also been shown to effectively inhibit p38 MAP kinase. We hypothesize that inhibiting DUSP26 will result in decreased NB cell growth in a p53 and/or p38-mediated manner. NSC-87877 (8-hydroxy-7-[(6-sulfo-2-naphthyl)azo]-5-quinolinesulfonic acid), a novel DUSP26 small molecule inhibitor, shows effective growth inhibition and induction of apoptosis in NB cell lines. NB cell lines treated with small hairpin RNA (shRNA) targeting DUSP26 also exhibit a proliferation defect both in vitro and in vivo. Treatment of NB cell lines with NSC-87877 results in increased p53 phosphorylation (Ser37 and Ser46) and activation, increased activation of downstream p38 effector proteins (heat shock protein 27 (HSP27) and MAP kinase-activated protein kinase 2 (MAPKAPK2)) and poly ADP ribose polymerase/caspase-3 cleavage. The cytotoxicity resulting from DUSP26 inhibition is partially reversed by knocking down p53 expression with shRNA and also by inhibiting p38 activity with SB203580 (4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine). In an intrarenal mouse model of NB, NSC-87877 treatment results in decreased tumor growth and increased p53 and p38 activity. Together, these results suggest that DUSP26 inhibition with NSC-87877 is an effective strategy to induce NB cell cytotoxicity in vitro and in vivo through activation of the p53 and p38 mitogen-activated protein kinase (MAPK) tumor-suppressor pathways.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / enzymology
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Brain Neoplasms / genetics
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Brain Neoplasms / pathology
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Line, Tumor
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Dual-Specificity Phosphatases / antagonists & inhibitors*
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Dual-Specificity Phosphatases / genetics
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Dual-Specificity Phosphatases / metabolism
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Enzyme Inhibitors / pharmacology*
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Female
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Gene Expression Regulation, Neoplastic*
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HSP27 Heat-Shock Proteins / genetics
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HSP27 Heat-Shock Proteins / metabolism
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Heat-Shock Proteins
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Humans
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Imidazoles / pharmacology
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Kidney / drug effects
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Kidney / enzymology
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Kidney / pathology
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinase Phosphatases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase Phosphatases / genetics
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Mitogen-Activated Protein Kinase Phosphatases / metabolism
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Molecular Chaperones
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Neuroblastoma / drug therapy*
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Neuroblastoma / enzymology
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Neuroblastoma / genetics
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Neuroblastoma / pathology
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Pyridines / pharmacology
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Quinolines / pharmacology*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Xenograft Model Antitumor Assays
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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HSP27 Heat-Shock Proteins
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HSPB1 protein, human
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Heat-Shock Proteins
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Imidazoles
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Intracellular Signaling Peptides and Proteins
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Molecular Chaperones
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NSC-87877
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Pyridines
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Quinolines
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RNA, Small Interfering
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Tumor Suppressor Protein p53
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Poly(ADP-ribose) Polymerases
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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p38 Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Phosphatases
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DUSP26 protein, human
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Dual-Specificity Phosphatases
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Caspase 3
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SB 203580