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

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 tranducers 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, electorphoretic 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. Prostate 42:88–98, 2000. © 2000 Wiley‐Liss, Inc.