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.