Suppressors of cytokine signalling (SOCS) are induced by interleukins (ILs) and various peptide hormones and may prevent sustained activation of signalling pathways. We have previously shown that SOCS-3 antagonizes regulation of cellular events by cAMP and is expressed in human prostate cancer. To investigate possible effects of androgen on SOCS-3 protein expression, two prostate cancer cell lines (PC3-AR and LAPC4) were treated with different concentrations of R1881. Western blot analyses revealed induction of SOCS-3 protein expression in both cell lines by androgen, an effect which can be blocked by the anti-androgen bicalutamide. To further characterize the effects of R1881 on the SOCS-3 gene, promoter-reporter assay and real-time PCR were performed. We found no influence of androgen on promoter activity or SOCS-3 mRNA levels, thus suggesting a post-transcriptional effect of androgen. Concordant with our previous findings, we show a significant increase of SOCS-3 protein after androgen treatment in cells in which transcription was blocked, but not in those with impaired translation. In order to understand implications of SOCS-3 regulation by androgen, we used SOCS-3-negative LNCaP-IL-6 cells and stably transfected them with a tetracycline-responsive SOCS-3 Tet-On plasmid. We report that androgenic effects on cell proliferation and prostate-specific antigen secretion are significantly diminished following up-regulation of SOCS-3. In conclusion, androgen up-regulates SOCS-3 protein via post-transcriptional effects. SOCS-3 inhibits androgen-stimulated proliferation by influencing cell cycle regulation. Taken together with previous findings showing androgen receptor activation by IL-6, our results imply that androgen and cytokine signalling pathways interact at multiple levels in prostate cancer.
ASJC Scopus subject areas
- Cancer Research
- Endocrinology, Diabetes and Metabolism