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

✍ Scribed by Spiotto, Michael T.; Chung, Theodore D.K.

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 486 KB
• Volume: 42
• Category: Article
• ISSN: 0270-4137
• DOI: 10.1002/(sici)1097-0045(20000201)42:2<88::aid-pros2>3.0.co;2-p

✦ Synopsis

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.