Proinflammatory cytokine interleukin-6 in prostate carcinogenesis

Interleukin-6 (IL-6) is a multifunctional pro-inflammatory cytokine which is expressed in clinical specimens obtained from patients with prostate cancer and in multiple cell lines. IL-6 expression is regulated in prostate cancer by several oncogenes and tumor suppressors. IL-6 activates in prostate cancer pathways of Janus kinases/signal transducers and activators of transcription (STAT), mitogen-activated protein kinases, and phosphatidylinositol 3-kinase. In several tumor models, proliferative and anti-apoptotic effects were described, although androgen-sensitive prostate cancer cells LNCaP are inhibited by IL-6. IL-6 is also involved in regulation of neuroendocrine differentiation and angiogenesis in prostate cancer. IL-6 activation of the androgen receptor is important for tumor growth and differentiation. IL-6 activation of STAT3 is crucial for maintenance of the tumor progenitor cells phenotype. Suppressors of cytokine signaling inhibit permanent activation of STAT3, however they may have also IL-6-independent effects. Experimental therapies with aim to inhibit IL-6 signaling in prostate cancer were developed with the monoclonal antibody CNTO328. Although progression towards castration resistance was delayed by CNTO328 in a xenograft model, clinical monotherapies in patients with castration therapy-resistant disease with the antibody did not yield a satisfactory response.