C/EBPdelta 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/EBPdelta gene expression and growth inhibition of human prostate cancer cells.


METHODS
Expression of C/EBPdelta and STAT3 activation were assayed using Northern and Western blotting techniques. Proliferation was assessed by [(3)H] thymidine incorporation, flow cytometry, and colony formation analyses. The analysis of the transcriptional regulation of C/EBPdelta 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/EBPdelta gene promoter and induces its expression. We also demonstrate that C/EBPdelta over-expression is capable of suppressing prostate cancer cell growth.


CONCLUSIONS
These results demonstrate that C/EBPdelta gene expression is increased in IL-6 treated LNCaP cells. Increased C/EBPdelta 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/EBPdelta controls prostate cancer cell growth and the potential role of C/EBPdelta in the survival and chemo resistance of prostate cancer metastasis. (c) 2004 Wiley-Liss, Inc.
Sanford
Daniel C
DC
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.
DeWille
James W
JW
D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D051743:CCAAT-Enhancer-Binding Protein-delta; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D053614:Janus Kinase 2; D008297:Male; D016254:Mutagenesis, Insertional; D011401:Promoter Regions, Genetic / Q000502:physiology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D022762:CCAAT-Enhancer-Binding Proteins; C497252:CEBPD protein, human; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D051743:CCAAT-Enhancer-Binding Protein-delta; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D013936:Thymidine