SOCS-3 and peptide hormone signaling in prostate cancer

Prostate cancer remains major health problem in the Western world for which there is no curative therapy if it is not detected in early stages. The levels of interleukin-6 (IL-6) are elevated in tissues and sera from prostate cancer patients. IL-6 may cause multifunctional responses through activation of different signaling pathways in target cells. Important regulators of the pathway of Janus kinases/signal transducers and activators of transcription factors are suppressors of cytokine signaling (SOCS). We found that SOCS-3, known as a tumor suppressor in several malignancies, is expressed in prostate cancer cells in which there is no phoshporylation of signal transducer and activator of transcription factor 3. There is also increased expression of SOCS-3 in malignant vs. benign prostate tissue. SOCS-3 antagonizes effects of cAMP on proliferation and apoptosis in prostate cancer cells. Principal investigator proposes to further study the mechanism by which SOCS-3 interferes with cAMP-regulated apoptosis. Studies will be also focused on a possible SOCS-3 effect of apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. For these experiments, PC3 cells transfected with SOCS-3 or control siRNA will be used. Well test the hypothesis that there is an interaction between death receptors and SOCS-3. In addition, well investigate whether SOCS-3 may inhibit action of fibroblast growth factors in target cells. For this purpose, the cells will be treated with fibroblast growth factors 2 or 6 after inhibition of SOCS-3 expression. Proliferation, migration, and invasion assays will be performed. Finally, well address the question whether SOCS-3 interferes with androgen receptor activation by androgen and/or IL-6. Androgen receptor shuttles between cytoplasm and nucleus and it is possible that SOCS-3 prevents its nuclear translocation. Taken together, proposed experiments should improve knowledge on effects of SOCS-3 in regulation of cellular events and clarify its importance for novel prostate cancer experimental therapy approaches.

Prostate cancer is one of the most common cancers in the Western world for which curative intervention is possible only in early stages. Cytokines have a role in prostate cancer development and may influence tumor growth and progression in different ways. In the present project we have investigated specific role of suppressors of cytokine signaling (SOCS) in prostate cancer. These molecules inhibit activation of signaling pathways of cytokines and, physiologically, may prevent chronic inflammation. In prostate cancer cells which do not respond to androgens SOCS-3 acts as an inhibitor of apoptosis. Moreover, SOCS-3 is highly expressed in cancer specimens obtained from patients who do not respond to therapy. We also found that SOCS-3 may exert the effects through regulation of the oncogene Bcl-2. SOCS-3 may be also important in prevention of prostate cancer. It antagonizes the effects of TRAIL and resveratrol. TRAIL is considered to be a tumor-specific pro-apoptotic agent and resveratrol is considered for cancer chemoprevention. Interestingly, we also found that SOCS-3 does not only inhibit transcription factor STAT3 but also phosphorylation of mitogen-activated protein kinases in the presence of fibroblast growth factor-2. This project provides evidence that molecules which are involved in regulation of inflammatory response may have multiple effects in prostate cancer. The results may have implications for development of novel targeted therapies in this common tumor.