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Clin Cancer Res ; 7(6): 1773-81, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11410519

ABSTRACT

Interleukin-6 (IL-6) induces prostate cancer (CaP) cell proliferation in vitro. Several lines of evidence suggest that IL-6 may promote CaP progression through induction of an androgen response. In this work, we explored whether IL-6 induces androgen responsiveness through modulation of androgen receptor (AR) expression. We found that in the absence of androgen, IL-6 increased prostate-specific antigen (PSA) mRNA levels and activated several androgen-responsive promoters, but not the non-androgen responsive promoters in LNCaP cells. Bicalutamide, an antiandrogen, abolished the IL-6 effect and IL-6 could not activate the PSA and murine mammary tumor virus reporters in AR-negative DU-145 and PC3 cells. These data indicate the IL-6 induces an androgen response in CaP cells through the AR. Pretreatment of LNCaP cells with SB202190, PD98059, or tyrphostin AG879 [p38 mitogen-activated protein kinase (MAPK), MAP/extracellular signal-regulated protein kinase kinase 1/2, and ErbB2 MAPK inhibitors, respectively) but not wortmannin (PI3-kinase inhibitor) blocked IL-6-mediated induction of the PSA promoter, which demonstrates that IL-6 activity is dependent on a MAPK pathway. Finally, IL-6 activated the AR gene promoter, resulting in increased AR mRNA and protein levels in LNCaP cells. These results demonstrate that IL-6 induces AR expression and are the first report of cytokine-mediated induction of the AR promoter. Taken together, our results suggest that IL-6 induces AR activity through both increasing AR gene expression and activating the AR in the absence of androgen in CaP cells. These results provide a mechanism through which IL-6 may contribute to the development of androgen-independent CaP.


Subject(s)
Interleukin-6/metabolism , Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , Up-Regulation , Anilides/pharmacology , Blotting, Western , Cell Nucleus/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Fluorescent Antibody Technique, Indirect , Gammaretrovirus/metabolism , Humans , Imidazoles/pharmacology , Interleukin-6/biosynthesis , Interleukin-6/pharmacology , Male , Microscopy, Fluorescence , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Nitriles , Plasmids/metabolism , Promoter Regions, Genetic , Prostate-Specific Antigen/biosynthesis , Prostate-Specific Antigen/genetics , Pyridines/pharmacology , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tosyl Compounds , Transcriptional Activation , Transfection , Tumor Cells, Cultured , Tyrphostins/pharmacology
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