Abstract
The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Benzamides / pharmacology*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cellular Senescence / drug effects*
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Enzyme Activation / drug effects*
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / metabolism
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Genes, ras / physiology*
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Histone Deacetylase Inhibitors
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Humans
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Insulin-Like Growth Factor I / pharmacology
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Naphthols / pharmacology*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Plasminogen Activator Inhibitor 1 / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, IGF Type 1 / metabolism
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Signal Transduction / drug effects*
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Sirtuin 1
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Sirtuins / antagonists & inhibitors
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Tumor Cells, Cultured
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Tyrosine / metabolism
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beta-Galactosidase / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Benzamides
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Histone Deacetylase Inhibitors
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Naphthols
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Plasminogen Activator Inhibitor 1
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sirtinol
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Tyrosine
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Epidermal Growth Factor
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Insulin-Like Growth Factor I
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Phosphatidylinositol 3-Kinases
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ErbB Receptors
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Receptor, IGF Type 1
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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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p38 Mitogen-Activated Protein Kinases
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beta-Galactosidase
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SIRT1 protein, human
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Sirtuin 1
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Sirtuins