C/EBPδ is a downstream mediator of IL-6 induced growth inhibition of prostate cancer cells

BACKGROUND. Although a number of reports have investigated the effects of IL-6 family cytokines on prostate cell growth, there is limited information available identifying IL-6 inducible downstream effector genes and their function in growth control. Previous studies have demonstrated that IL-6 treatment results in the activation of signal transducer and activator of transcription3 (STAT3) in prostate cancer cells. The goal of this study was to investigate the influence of IL-6 treatment and activation of the Jak/STAT signal transduction pathway on C/EBP delta gene expression and growth inhibition of human prostate cancer cells. METHODS. Expression of C/EBP delta and STAT3 activation were assayed using Northern and Western blotting techniques. Proliferation was assessed by [H-3] thymidine incorporation, flow cytometry, and colony formation analyses. The analysis of the transcriptional regulation of C/EBP delta was performed using luciferase-reporter constructs. RESULTS. In this report, we demonstrate that IL-6 treatment induces STAT3 activation (pSTAT3), pSTAT3 binds to the human C/EBP delta gene promoter and induces its expression. We also demonstrate that C/EBP delta over-expression is capable of suppressing prostate cancer cell growth. CONCLUSIONS. These results demonstrate that C/EBP delta gene expression is increased in IL-6 treated LNCaP cells. Increased C/EBP delta gene expression plays an important role in IL-6/STAT3 mediated growth arrest of LNCaP prostate cancer cells. Ongoing studies are investigating the mechanism by which C/EBP delta controls prostate cancer cell growth and the potential role of C/EBP delta in the survival and chemo resistance of prostate cancer metastasis. (c) 2004 Wiley-Liss, Inc.