Interleukin-6 regulates androgen receptor activity and prostate cancer cell growth.
Interleukin-6 (IL-6) is a multifunctional cytokine which is involved in regulation of growth of various malignant tumors. IL-6 binds to its receptor, which is composed of a ligand-binding and a signal-transducing subunit and activates pathways of signal transducers and activators of transcription and mitogen-activated protein kinases (MAPKs). In prostate cancer cells, IL-6 induces divergent proliferative responses. Serum levels of IL-6 are elevated in patients with therapy-resistant carcinoma of the prostate. We have investigated whether IL-6 interacts with the androgen signaling pathway in prostate cancer cells. In DU-145 cells, transiently transfected with androgen receptor (AR) cDNA, IL-6 caused ligand-independent and synergistic activation of the AR. Nonsteroidal antagonists of the AR down-regulated AR activity induced by IL-6. In LNCaP cells, IL-6-induced expression of the AR-regulated prostate-specific antigen gene. Inhibitors of protein kinase A and C and MAPK down-regulated IL-6-induced AR activity. IL-6 expression in human prostate tissue was studied by immunohistochemistry. In benign prostatic tissue, IL-6 immunoreactivity was confined to basal cells. In prostate intraepithelial neoplasia and in cancer tissue, atypical intraluminal and cancer cells expressed IL-6. The expression of IL-6 receptor was demonstrated in benign and malignant tissue in both epithelium and stroma. In the authors' laboratory, IL-6-inhibited proliferation of parental LNCaP cells. A new LNCaP subline was generated to investigate changes in signal transduction which might occur after prolonged treatment with IL-6. In the subline LNCaP-IL-6+, IL-6 neither reduced a number of cells nor caused G1 growth arrest. IL-6 receptor expression declined during long-term IL-6 treatment. However, IL-6-up-regulated AR expression and was capable of inducing AR activity in LNCaP-IL-6+ cells. Parental LNCaP cells do not express IL-6. In contrast, IL-6 mRNA and protein expression were detectable in high passages of LNCaP-IL-6+ cells. Thus changes in signal transduction occur in prostate cancer cells after prolonged IL-6 treatment
Culig
Zoran
Z
Department of Urology, University of Innsbruck, A-6020 Innsbruck, Austria. zoran.culig@uibk.ac.at
Bartsch
Georg
G
Hobisch
Alfred
A
D002454:Cell Differentiation / Q000502:physiology; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; D011944:Receptors, Androgen