Abstract
Apoptosis is regulated by a series of biochemical events that commits a cell to death. We are interested in understanding and have been investigating the mechanisms by which nitric oxide (NO) induces apoptosis in human breast cancer cell lines. In this study, we investigated the possible interplay of extracellular signal-regulated kinase (ERK) and Akt pathways in NO-induced apoptosis. MKP-1 transcripts were induced in these cells as early as 4 h, peaking at 8 h leading to inactivation of ERK1/2 at 16-24 h after exposure to NO. We also found 50% decrease in the levels pAkt at 24 h of DETA-NONOate treatment. The inactivation of ERK1/2 preceded the dephosphorylation of Akt and apoptosis. NO was not able to inactivate ERK1/2 or Akt or to induce apoptosis in the presence of a phosphatase inhibitor, sodium orthovanadate, or antisense oligonucleotides, suggesting a cross-talk between the two pathways. NO also up-regulated MKP-1 in another breast cancer cell line, ZR 75-30, which led to inactivation of ERK1/2 and induced apoptosis. In MDA-MB-231, NO did not induce MKP-1, and there was no ERK inactivation or apoptosis. Our results indicate that expression of MKP-1 by NO leading to dephosphorylation of ERK1/2 is the initial essential event that commits the cells to the apoptotic pathway in breast cancer cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / enzymology*
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Breast Neoplasms / pathology*
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Cell Cycle Proteins*
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Cell Line, Tumor
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Dual Specificity Phosphatase 1
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Enzyme Induction / drug effects
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Humans
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Immediate-Early Proteins / biosynthesis
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Immediate-Early Proteins / metabolism*
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism*
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Nitric Oxide / pharmacology*
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Nitric Oxide Donors / pharmacology*
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Nitroso Compounds / pharmacology*
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Phosphoprotein Phosphatases*
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Phosphorylation / drug effects
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Protein Phosphatase 1
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Protein Serine-Threonine Kinases*
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Protein Tyrosine Phosphatases / biosynthesis
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Protein Tyrosine Phosphatases / metabolism*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
Substances
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Cell Cycle Proteins
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Immediate-Early Proteins
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Nitric Oxide Donors
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Nitroso Compounds
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Proto-Oncogene Proteins
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2,2'-(hydroxynitrosohydrazono)bis-ethanamine
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Nitric Oxide
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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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