Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells.
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.
Chen
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Intramural Research Support Program, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702, USA.
Wang
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LH
Farrar
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D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins; D020218:Response Elements / Q000235:genetics; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D045165:Testosterone Congeners / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D015741:Metribolone; D020928:Mitogen-Activated Protein Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D045165:Testosterone Congeners; D015534:Trans-Activators; D000093242:Interleukin-6 Inhibitors; C108944:SOCS1 protein, human; C106643:SOCS2 protein, human; C494086:STAT3 protein, human; C507924:JAK2 protein, human