Interleukin-6 and Suppressor of cytokine signaling-3 in regulation of proliferation and apoptosis in human prostate cancer

Interleukin-6 (IL-6) and its receptor are highly expressed in human prostate cancer. IL-6 effects are mediated through signaling pathways of Janus kinases (JAK)/signal transducers and activators of transcription /STAT) factors, mitogen-activatedprotein kinases (MAPK), or phosphoinositol 3-kinase in a cell type-specific manner. IL-6 regulates expression of prostate-specific antigen through activation of the androgen receptor. Growth of most prostate cancer cell lines is up-regulated by IL-6 in an autocrine manner. However, parental LNCaP cells are inhibited by IL-6 that diminishes expression of cyclin-dependent kinases and up-regulates that of tumor suppressors. We have established a novel LNCaP subline (LNCaP-IL-6+) after prolonged treatment with IL-6. In contrast to their counterparts cultured in the absence of IL-6 (LNCaP-IL-6-), LNCaP-IL-6+ acquire growth advantage. We have observed stimulation of phosphorylation of STAT3 solely in LNCaP-IL-6-, whereas proliferation of LNCaP-IL-6+ could be explained by activation of the MAPK pathway. To improve understanding of regulation of the JAK/ STAT pathway in prostate cancer cells, we have investigated expression of suppressor of cytokine signaling (SOCS)-3. Interestingly, we found that SOCS-3 is constitutively expressed in all prostate cancer cell lines that are STAT3-negative (i.e. cell lines with exemption of LNCaP and LNCaP-IL-6-). In those cells, expression of SOCS-3 increases after treatment with a demethylating agent. SOCS-3 was detectable by immunohistochemistry in premalignant and malignant lesions, whereas there was only a weak positive reaction in benign tissue. Expression of SOCS-3 in prostate cancer cells is up-regulated by a cAMP derivative. Most interestingly, siRNA experiments showed that SOCS-3 antagonizes a negative regulation of proliferation and induction of apoptosis by cAMP in prostate cancer cells. Taken together, our results show that IL-6 is in most prostate cancers a target for novel therapies. SOCS-3 appears to be a critical mediator that regulates IL-6 signaling.