Abstract
Histone deacetylase inhibitors (HDACi) comprise a family of chemotherapeutic agents used in the clinic to treat cutaneous T-cell lymphoma and tested for the therapy of other malignancies. Previous reports have shown that eIF2α phosphorylation is induced upon treatment with HDACi. However the kinase responsible for this phosphorylation or the biological significance of this finding is not yet established. Herein, we show that eIF2α phosphorylation is not attributed to a specific eIF2α kinase, but rather different eIF2α kinases contribute to its upregulation in response to the HDACi, vorinostat. More importantly our data indicate that eIF2α phosphorylation acts in a cytoprotective manner, whereas the eIF2α kinases PKR and GCN2 promote vorinostat-induced apoptosis. These results reveal a dual nature for eIF2α kinases with potential implications in the treatment with histone deacetylase inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution / genetics
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Caspase 3 / metabolism
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Cell Line, Tumor
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Cells, Cultured
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Eukaryotic Initiation Factor-2 / genetics
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Eukaryotic Initiation Factor-2 / metabolism
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Hep G2 Cells
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Histone Deacetylase Inhibitors / pharmacology*
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Humans
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Hydroxamic Acids / pharmacology
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Mice
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Mice, Knockout
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Phosphorylation / drug effects
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Phosphorylation / genetics
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Vorinostat
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eIF-2 Kinase / genetics
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eIF-2 Kinase / metabolism*
Substances
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Eukaryotic Initiation Factor-2
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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trichostatin A
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Vorinostat
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Eif2ak4 protein, mouse
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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Casp3 protein, mouse
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Caspase 3