Interleukin-6 and prostate cancer: Current developments and unsolved questions
Introduction
Recent investigations have resulted in identification of a large number of potential targets for prostate cancer (PCa) therapy. Although established therapies target the androgen receptor (AR) or elements of the AR signaling pathway, it is clear that several molecules regulated by cytokines contribute to growth at different stages of prostate carcinogenesis. The oncogenic role of inflammatory cytokines has been studied in PCa in different human and animal models and experimental settings. In most studies, signal transduction and effects on proliferation and apoptosis by interleukin (IL)-6, −8, and −4 have been investigated. The role of IL-6 in PCa is particularly interesting because of its association with multiple signaling pathways, as well as different regulation of proliferative and apoptotic responses. Thus, there is great potential for therapeutic intervention. Although results of preclinical research have provided encouraging data related to potential anti-IL-6 strategies, translation of these findings into clinical practice is still associated with considerable difficulties. Recent studies have therefore focused on the role of endogenous inhibitors of cytokine signaling in PCa. In this review, these topics will be primarily addressed and discussed. Basic knowledge of IL-6 signal transduction and regulation of cellular events in PCa have been summarized previously (Culig and Puhr, 2012). A central role in regulation of the inflammatory responses in PCa could be attributed to signal transducer and activator of transcription (STAT) factor-3. It is regulated not only in response to IL-6, but also by other cytokines such as IL-11 and epidermal growth factor (EGF) in the tumor and in the tumor micro-environment. In this updated review, we analyze recent developments in the field and discuss problems as well as perspectives of IL-6 targeted PCa therapies.
Section snippets
IL-6: a therapeutic target or tumor suppressor in PCa
Prostate carcinogenesis and progression are determined by the presence and activation status of the AR. Its activation in normal and pathological conditions can be potentiated by numerous co-activators that interact with one or more domains of the receptor. AR expression is increased in castration resistant PCa (CRPC) due to gene amplification or protein stabilization. Mutant receptors may be activated by various steroids and anti-hormones, thus contributing to accelerated tumor growth.
IL-6 and AR activation
PCa progression is dependent on an active role of the AR. For example, a derivative of LNCaP, C4-2 cells, exhibit high levels of AR although they cannot be regulated by androgenic hormones. Many investigators focused on expression and activation of truncated AR which is constitutively active thus contributing to failure of treatment with inhibitors of androgen synthesis and 2nd generation anti-androgens. Among other mechanisms, ligand-independent activation of the AR has been intensively
IL-6 in regulation of PCa stemness
It is widely accepted that tumor-initiating cells with stem cell characteristics are associated with therapy resistance, as they can not be targeted by conventional endocrine, chemo- or radiotherapies. Their function has to be analyzed in appropriate cellular models, some of which are being developed. Because of a rare appearance of stem or “stem cell like” cells, it is difficult to precisely quantify them in tumor samples. In prostate and in other malignancies, the signaling pathway of Janus
Translational anti-IL-6 therapies in PCa
Therapeutic approaches in PCa could be focused on IL-6 itself, the JAK/STAT3 pathway, or specifically STAT3. The outcome of these different therapies may not necessarily be the same and depends on interaction with other pathways as well as on drug pharmacokinetics and pharmacodynamics.
Several laboratories tested the monoclonal antibody CNTO 328 (siltuximab) for a potential anti-IL-6 approach so far. PC3 and DU145 cells, which express high levels of the cytokine, could be inhibited in vitro and
Endogenous inhibitors of cytokine signaling
Persistent activation of STAT3 in target tissues could be prevented by endogenous inhibitors of cytokine signaling. They are known as suppressors of cytokine signaling (SOCS) or protein inhibitors of activated STAT (PIAS). SOCS are rapidly induced by cytokines and may achieve their action at different levels. There are substantial differences in SOCS3 expression between AR-positive and –negative cells. In AR-negative cells, a high expression of SOCS3 could be explained by endogenous IL-6
Challenges for future research
Although results of preclinical studies with the anti-IL-6 antibody siltuximab suggested that IL-6 and downstream signaling pathways should be targeted in PCa, translation of these findings in clinic has been associated with difficulties. Several issues have to be addressed in order to improve IL-6 targeted therapy. Biomarkers that may allow selection of patients who may benefit are still not available. Critical issues related to this novel therapy are appropriate selection of patients and
Declaration of interest
The authors do not have a conflict of interest in relation to preparation of this article.
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