Abstract
Interleukin 6 (IL-6) is a cytokine that regulates not only immune and inflammatory responses but also the growth of some tumors, including prostate carcinomas. IL-6 signals through Janus kinase, signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinase and is also able to induce androgen receptor (AR)-mediated gene activation in prostate cancer, which is an important process in prostate cancer androgen-independent progression. We now show that IL-6-induced AR-mediated gene activation requires the activation of STAT3 by IL-6 in LNCaP prostate cancer cells. In particular, STAT3 associates with AR in an androgen-independent but IL-6-dependent manner. Inhibition of STAT3 rather than mitogen-activated protein kinase results in inhibition of AR-mediated gene activation in response to IL-6. These findings not only identify STAT3 as an important signaling molecule required for IL-6-signaling to induce AR-mediated gene activation in prostate carcinoma cells but also reveal the importance of activated STAT3 in human tumor development and progression.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Disease Progression
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Enzyme Activation / drug effects
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Gene Expression Regulation, Neoplastic / drug effects*
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Genes, Reporter / genetics
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Humans
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / pharmacology*
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Intracellular Signaling Peptides and Proteins*
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Janus Kinase 2
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Male
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Metribolone / pharmacology
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Mutation / genetics
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Prostatic Neoplasms / enzymology
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism
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Protein Binding / drug effects
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism
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Proteins / genetics
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Proteins / metabolism
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Proto-Oncogene Proteins*
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Receptors, Androgen / metabolism*
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Repressor Proteins*
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Response Elements / genetics
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STAT3 Transcription Factor
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Signal Transduction / drug effects*
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Testosterone Congeners / pharmacology
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcriptional Activation
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Transfection
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Tumor Cells, Cultured
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Proteins
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Proto-Oncogene Proteins
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Receptors, Androgen
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Repressor Proteins
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SOCS1 protein, human
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SOCS2 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Testosterone Congeners
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Trans-Activators
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Metribolone
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Janus Kinase 2
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Mitogen-Activated Protein Kinases