Abstract
Androgen receptor (AR) plays an important role in the development and progression of prostate cancer upon the action of androgen through the binding of the androgen-responsive elements (AREs) on the target genes. Abnormal activation of the AR by nonandrogen has been implicated in the progression of androgen-independent prostate cancer. The levels of interleukin-4 (IL-4) are significantly elevated in sera of patients with hormone refractory prostate cancer. The potential role of IL-4 on the activation of AR was investigated in prostate cancer cells. IL-4 enhances AR-mediated prostate-specific antigen (PSA) expression and ARE-containing gene activity through activation of the AR in the androgen ablation condition in human prostate cancer cells. The AR can also be sensitized by IL-4 and activated by significantly lower levels of androgen (10 pM of R1881) in prostate cancer cells. IL-4 enhances nuclear translocation of AR and increases binding of the AR to the ARE in LNCaP prostate cancer cells. Blocking of the Akt pathway by an Akt-specific inhibitor LY294002 abrogates IL-4-induced PSA expression and AR signaling. These results demonstrate that IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells. Understanding IL-4-induced signaling leading to abnormal activation of AR will provide insights into the molecular mechanisms of androgen-independent progression of prostate cancer cells.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Androgen Antagonists / pharmacology
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Chromones / pharmacology
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / metabolism
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Enzyme Inhibitors / pharmacology
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Flutamide / pharmacology
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Gene Expression / drug effects
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Humans
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Interleukin-4 / metabolism
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Interleukin-4 / pharmacology*
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Male
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Metribolone / pharmacology
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Prostate-Specific Antigen / drug effects
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Prostate-Specific Antigen / genetics
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Prostate-Specific Antigen / metabolism*
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / drug effects
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Receptors, Androgen / drug effects
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism*
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Response Elements / drug effects
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Signal Transduction / drug effects*
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Testosterone Congeners / pharmacology
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Tumor Cells, Cultured
Substances
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Androgen Antagonists
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Chromones
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Enzyme Inhibitors
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Androgen
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Testosterone Congeners
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Interleukin-4
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Metribolone
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Flutamide
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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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Prostate-Specific Antigen