SOCS-3 and prostate cancer progression

Therapy for advanced prostate cancer, androgen ablation, is palliative. Although there is an improvement in understanding of mechanisms involved in tumor progression, there is little success in development of novel therapies. Median prolongation of life of patients who use docetaxel, a compound that blocks mitosis by inhibiting mitotic spindle assembly, is two to three months only. Several proinflammatory cytokines are involved in prostate tumorigenesis and progression. Cytokines such as interleukin-6 may display multifunctional effects on tumor cells. They activate signaling pathways of Janus kinases/signal transducers and activators of transcription, mitogen-activated protein kinase, and phosphoinositol 3- kinase in a cell type-dependent manner. Suppressor of cytokine signaling-3 (SOCS-3) that inhibits activation of the signaling pathway of Janus kinases/signal transducers and activator of transcription is highly expressed in prostate cancer and is implicated in stimulation of proliferation and inhibition of apoptosis. This project should explore the mechanisms by which SOCS-3 contributes to tumor progression and provide a basis for a more efficient therapy in patients with prostate cancer. On the basis of the Prinicipal Investigator`s data published between 2006 and 2010, it is hypothesized that modulation of SOCS-3 expression in prostate cancer in selected cell lines will improve understanding of mechanisms relevant to tumor progression. To achieve this goal, in vitro and in vivo experiments will be performed. Specific aims of the project are: 1. to understand the mechanism by which SOCS-3 inhibits AR activity 2. to evaluate the role of SOCS-3 in the development of therapy resistance in prostate cancer 3. to improve understanding of contribution of SOCS-3 to development of refractoriness to docetaxel in prostate cancer

Proinflammatory cytokines have an important role in progression of prostate cancer. Suppressors of cytokine signalling (SOCS) regulate phosphorylation of STAT3 after treatment with IL-6. In this project we could show that the expression of SOCS-3 in androgen-sensitive cells is very low. In prostate cancer patient tissues, the expression of SOCS-3 is very heterogenous. Treatment with IL-6 leads to a considerable increase of SOCS-3 expression. We demonstrated that androgenic treatment leads to a decrease in SOCS-3 mRNA expression. Antiandrogens, such as enzalutamide, which are used in prostate cancer treatment, could stimulate expression of SOCS-3. Modulation of SOCS-3 expression influences stem cell/tumor initiating cell antigens. Therefore, we propose that SOCS-3 may have an important role in prostate cancer progression and therapy resistance.