ag-879 and Prostatic-Neoplasms

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.

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

Overexpression of the HER2/Neu protooncogene has been linked to the progression of breast cancer. Here we demonstrate that the growth of prostate cancer LNCaP cells can also be increased by the stable transfection of HER2/Neu. Using AG879, a HER2/Neu inhibitor, and PD98059, a MAP kinase inhibitor, as well as MAP kinase phosphatase-1 (MPK-1), in the transfection assay, we found that HER2/Neu could induce prostate-specific antigen (PSA), a marker for the progression of prostate cancer, through the MAP kinase pathway at a low androgen level. Reporter assays and mammalian two-hybrid assays further suggest this HER2/Neu-induced androgen receptor (AR) transactivation may function through the promotion of interaction between AR and AR coactivators, such as ARA70. Furthermore, we found this HER2/Neu --> MAP kinase --> AR-ARAs --> PSA pathway could not be blocked completely by hydroxyflutamide, an antiandrogen used in the treatment of prostate cancer. Together, these data provide a novel pathway from HER2/Neu to AR transactivation, and they may represent one of the reasons for the PSA re-elevation and hormone resistance during androgen ablation therapy in prostate cancer patients.

Topics: Androgen Antagonists; Androgens; Calcium-Calmodulin-Dependent Protein Kinases; Cell Division; Flavonoids; Flutamide; Gene Expression Regulation, Neoplastic; Humans; Male; Mutagenesis, Site-Directed; Nuclear Receptor Coactivators; Oncogene Proteins; Prostate-Specific Antigen; Prostatic Neoplasms; Receptor, ErbB-2; Receptors, Androgen; Signal Transduction; Trans-Activators; Transcription Factors; Transcriptional Activation; Transfection; Tumor Cells, Cultured; Tyrphostins