IL-6/IL-6R as a potential key signaling pathway in prostate cancer development

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in prostate regulation and in prostate cancer (PC) development/progression. IL-6 acts as a paracrine and autocrine growth stimulator in benign and tumor prostate cells. The levels of IL-6 and respective receptors are increased during prostate carcinogenesis and tumor progression. Several studies reported that increased serum and plasma IL-6 and soluble interleukin-6 receptor levels are associated with aggressiveness of the disease and are associated with a poor prognosis in PC patients. In PC treatment, patients diagnosed with advanced stages are frequently submitted to hormonal castration, although most patients will eventually fail this therapy and die from recurrent castration-resistant prostate cancer (CRPC). Therefore, it is important to understand the mechanisms involved in CRPC. Several pathways have been proposed to be involved in CRPC development, and their understanding will improve the way to more effective therapies. In fact, the prostate is known to be dependent, not exclusively, on androgens, but also on growth factors and cytokines. The signaling pathway mediated by IL-6 may be an alternative pathway in the CRPC phenotype acquisition and cancer progression, under androgen deprivation conditions. The principal goal of this review is to evaluate the role of IL-6 pathway signaling in human PC development and progression and discuss the interaction of this pathway with the androgen recepto pathway. Furthermore, we intend to evaluate the inclusion of IL-6 and its receptor levels as a putative new class of tumor biomarkers.The IL-6/IL-6R signaling pathway may be included as a putative molecular marker for aggressiveness in PC and it may be able to maintain tumor growth through the AR pathway under androgen-deprivation conditions. The importance of the IL-6/IL-6R pathway in regulation of PC cells makes it a good candidate for targeted therapy.

Keywords: Androgen receptor; Castration-resistant prostate cancer; Hormonal castration; Inteuleukin-6; Inteuleukin-6 receptor; Prostate cancer; Tumor biomarker.

Figure 1

Schematic of IL-6 classical and trans-signaling pathway. IL-6: Interleukin 6; JAK: Janus kinase; MAPK: Mitogen-activated protein kinase; PI3K; Phosphatidylinositol 3-kinase; RANKL: Receptor activator of nuclear factor κB ligand; sIL-6R: Soluble IL-6 receptor; STAT3: Signal transducer and activator of transcription 3.

Figure 2

Hypothetical representation of AR pathway regulation by IL-6 in prostate cancer cells. IL-6: Interleukin 6; MAPK: Mitogen-activated protein kinase; STAT3: Signal transducer and activator of transcription 3; AR: Androgen receptor; PSA: Prostate-specific antigen.