Interleukin-6 and prostate cancer: Current developments and unsolved questions

• Published in: Molecular and cellular endocrinology Vol. 462; no. Pt A; pp. 25 - 30
• Main Authors: Culig, Zoran, Puhr, Martin
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 15.02.2018
• Subjects: angiogenesis; Antibodies; apoptosis; Cancer progression; castration; cell growth; humans; Interleukin-6; metastasis; mice; neoplasm cells; non-specific protein-tyrosine kinase; patients; phosphorylation; prostatic neoplasms; signal transduction; STAT3; Therapy; transactivators; Antibodies; Therapy; Cancer progression; STAT3; Interleukin-6
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2017.03.012

Interleukin (IL)-6 is a pro-inflammatory cytokine that is expressed in prostate tumors and in the stromal tumor micro-enviroment. It is known to regulate proliferation, apoptosis, angiogenesis, and differentiation. The signaling pathway of Janus kinase and signal transducer and activator of transcription (STAT)3, which is activated by IL-6, is in the focus of scientific investigations for improved treatment approaches. Different effects of IL-6 and/or STAT3 on tumor cell growth have been observed in human and murine prostate cancer (PCa) models. Experimental therapies have been proposed in order to block the IL-6/STAT3 signaling pathway. In this context, the anti-IL-6 antibody siltuximab (CNTO 328) has been demonstrated to inhibit growth of prostate tumors in vitro and in vivo and delays progression towards castration resistance. However, clinically, the anti-IL-6 antibody was not successful as a monotherapy in phase II studies in patients with metastatic PCa. IL-6 is implicated in regulation of cellular stemness by increasing phosphorylation of STAT3. The cytokine has also a role in development of resistance to the non-steroidal anti-androgen enzalutamide. Endogenous inhibitors of IL-6 are suppressors of cytokine signaling and protein inhibitors of activated STAT. Although they inhibit signal transduction through STAT3, they may also exhibit anti-apoptotic effects. On the basis of complexity of IL-6 action in PCa, an individualized approach is needed to identify patients who will benefit from anti-IL-6 therapy in combination with standard treatments. •IL-6 exerts oncogenic effects in most prostate cancers and activates multiple signaling pathways.•Therapeutic intervention is based on inhibition of IL-6 itself or the STAT3 pathway.•Translation of experimental therapy studies has a very limited success.•Future experimental anti-IL-6 and anti-STAT3 therapies may target stem cells.