STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP

Prostate. 2000 Feb 1;42(2):88-98. doi: 10.1002/(sici)1097-0045(20000201)42:2<88::aid-pros2>3.0.co;2-p.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / drug effects
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / physiology
  • Humans
  • Interleukin-6 / pharmacology*
  • Male
  • Phenotype
  • Prostatic Neoplasms / pathology*
  • STAT3 Transcription Factor
  • Signal Transduction*
  • Trans-Activators / biosynthesis*
  • Trans-Activators / physiology
  • Transcription, Genetic*
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • Interleukin-6
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators