title: STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP.
abstract: BACKGROUND
  In prostate cancer, we and others have observed distinct phenotypic responses to interleukin-6 (IL-6), which acts either as a paracrine growth inhibitor in the LNCaP cell line or as an autocrine growth stimulator in PC-3, DU145, and TSU cell lines. To understand the underlying mechanism responsible for this phenotypic difference, we investigated differences in the IL-6-induced Janus kinase-signal transducers and activators of transcription (JAK-STAT) signal transduction pathway between these two phenotypes.
  
  
  METHODS
  Prostate cancer cell lines were assayed for STAT3 activity by immunoblotting, electrophoretic gel shift assays (EMSA), and a luciferase reporter assay to test for STAT3 protein expression, phosphorylation, DNA binding, and transcriptional activity. To address the physiological role of STAT3, we introduced a dominant-negative mutant of STAT3 into LNCaP cells and assayed the effects of IL-6 on cell growth of this stable transfectant by cell counting, clonogenic assays, and c-myc expression.
  
  
  RESULTS
  IL-6 induced transcriptional activity of STAT3 only in LNCaP. STAT3 was transcriptionally inactive in PC-3, TSU, and DU145 at the level of protein expression, tyrosine phosphorylation, and DNA binding/transcriptional activity, respectively. An isolated LNCaP subclone containing a dominant-negative mutant of STAT3, LNCaP-SF, did not show STAT3-DNA binding or transcriptional activity. LNCaP-SF exhibited a proliferative response to IL-6 as compared to the control LNCaP-neo clone, which underwent growth arrest. Unlike LNCaP-neo, LNCaP-SF was able form colonies and to maintain c-myc expression in the presence of IL-6.
  
  
  CONCLUSIONS
  STAT3 transcriptional activation correlates with the growth-inhibitory signal of IL-6 in LNCaP, suggesting that STAT3 transcriptional activity is an important determinant in the different phenotypic responses to IL-6 in prostate cancer.
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, and the Pritzker School of Medicine, Chicago, Illinois 60637, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Spiotto
authors.forename: T D
authors.initials: TD
authors.lastname: Chung
mesh_terms: D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000473:pathology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis* / Q000502:physiology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators