Abstract
It has recently been shown that the androgen receptor (AR) is the main factor that required for prostate cancer cells survival. We show that knocking down AR expression by siRNA induces PI3K-independent activation of Akt, which was mediated by calcium/calmodulin-dependent kinase II (CaMKII). We further show, for the first time, that prostate cancer cells express beta,gamma and delta CaMKII genes, and the expression of these genes is under the control of AR activity: active AR in the presence of androgens inhibits CaMKII gene expression whereas inhibition of AR activity results in elevated level of kinase activity and in enhanced expression of CaMKII-beta and -gamma genes. Overexpression of CaMKII genes results in resistance to apoptosis induced by KN-93, a CaMKII inhibitor, or wortmanninn, a PI3K/Akt inhibitor, in combination with doxorubicin, thapsigargin and TRAIL. Moreover, overexpression of CaMKII increases secretion of prostate specific antigen and promotes cell growth of LNCaP in steroid-free condition. Our data show that there is cross-talk between AR- and CaMKII-mediated pathways. The results of this study suggest that CaMKII is an important player in prostate cancer cells ability to escape apoptosis under androgen ablation and facilitate the progression of prostate cancer cells to an androgen independent state.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Androgen Receptor Antagonists
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Androgens / deficiency
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Androstadienes / pharmacology
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis / drug effects*
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Benzylamines / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
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Doxorubicin / pharmacology
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Drug Therapy, Combination
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Enzyme Inhibitors / pharmacology
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Humans
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Immunosuppressive Agents / pharmacology
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Isoenzymes / metabolism
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Luciferases / metabolism
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Male
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Phosphatidylinositol 3-Kinases / metabolism
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Prostate-Specific Antigen / metabolism
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Prostatic Neoplasms / enzymology*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / pathology
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / pharmacology
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sulfonamides / pharmacology
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TNF-Related Apoptosis-Inducing Ligand / pharmacology
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Thapsigargin / pharmacology
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Tumor Cells, Cultured / drug effects
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Wortmannin
Substances
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AR protein, human
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Androgen Receptor Antagonists
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Androgens
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Androstadienes
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Antibiotics, Antineoplastic
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Benzylamines
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Enzyme Inhibitors
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Immunosuppressive Agents
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Isoenzymes
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Receptors, Androgen
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Sulfonamides
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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KN 93
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Thapsigargin
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Doxorubicin
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Luciferases
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Prostate-Specific Antigen
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Wortmannin