Abstract
The present report investigated the pathway(s) involved in the inhibition of apoptosis by the synthetic androgen, R1881 in serum-starved LNCaP cells exposed to the pi3K inhibitor, LY294002. R1881 blocked LY294002-induced apoptosis through the inhibition of Bak activation via an increase in Bcl-xL transcription and protein expression. In addition, R1881 treatment enhanced the stability of the Pim-1 kinase, resulting in the inhibition of the activation of the BH3-only protein Bad through its phosphorylation at ser75. Pharmacological inhibition of the Pim-1 kinase activity with quercetagetin, a highly selective Pim-1 inhibitor, prevented R1881-mediated increase in Bad phosphorylation and restored cell sensitivity to LY294002-induced apoptosis despite the increase in Bcl-xL expression. These results demonstrate for the first time that the inhibition of LY294002-induced apoptosis by androgen is a function of an androgen receptor-dependent genomic signaling pathway leading to an increase in Bcl-xL expression as well as a non-genomic, Pim-1-dependent, signaling pathway mediated via phosphorylation of Bad at ser75.
Copyright © 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androgens / pharmacology*
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Cell Line, Tumor
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Cell Survival / drug effects
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Chromones / antagonists & inhibitors
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Chromones / pharmacology
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Culture Media, Serum-Free
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Enzyme Activation / drug effects
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Enzyme Stability / drug effects
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Gene Expression Regulation / drug effects
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Half-Life
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Humans
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Metribolone / pharmacology*
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Morpholines / antagonists & inhibitors
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Morpholines / pharmacology
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-pim-1 / chemistry
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Proto-Oncogene Proteins c-pim-1 / metabolism*
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Serine / metabolism*
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Signal Transduction / drug effects
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bcl-2 Homologous Antagonist-Killer Protein / antagonists & inhibitors
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-Associated Death Protein / chemistry*
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bcl-Associated Death Protein / metabolism*
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bcl-X Protein / genetics
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bcl-X Protein / metabolism*
Substances
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Androgens
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Chromones
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Culture Media, Serum-Free
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Morpholines
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-Associated Death Protein
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bcl-X Protein
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Metribolone
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Serine
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-pim-1