Response to Androgens and Androgen Receptor Antagonists in the Presence of Cytokines in Prostate Cancer

Abstract

Simple Summary Prostate cancer is the most frequently diagnosed non-cutaneous tumor in men in the Western world. Therapy for non-organ confined prostate cancer includes anti-androgens such as bicalutamide, enzalutamide and darolutamide. The androgen receptor is expressed during tumor initiation and progression. Androgen receptor could be activated by interleukins, which are produced by blood cells and adjacent stroma. These cytokines may affect response of tumor cells to anti-androgenic drugs, which are commonly used in prostate cancer therapy. There are several experimental studies showing an effect of anti-cytokine therapies in prostate cancer. However, the clinical translation is limited and more clinical trials are needed to improve action of anti-androgens in prostate cells which are stimulated by cytokines. Abstract Non-steroidal anti-androgens have a major role in the treatment of non-localized prostate cancer. Interleukins are involved in the regulation of many cellular functions in prostate cancer and also modify cellular response to anti-androgens. A specific role of selected IL is presented in this review. IL-8 is a cytokine expressed in prostate cancer tissue and microenvironment and promotes proliferation and androgen receptor-mediated transcription. In contrast, IL-1 displays negative effects on expression of androgen receptor and its target genes. A subgroup of prostate cancers show neuroendocrine differentiation, which may be in part stimulated by androgen ablation. A similar effect was observed after treatment of cells with IL-10. Another cytokine which is implicated in regulation of androgenic response is IL-23, secreted by myeloid cells. Most studies on androgens and IL were carried out with IL-6, which acts through the signal transducer and activator of the transcription (STAT) factor pathway. IL-6 is implicated in resistance to enzalutamide. Activation of the STAT-3 pathway is associated with increased cellular stemness. IL-6 activation of the androgen receptor in some prostate cancers is associated with increased growth in vitro and in vivo. Molecules such as galiellalactone or niclosamide have an inhibitory effect on both androgen receptor and STAT-3 pathways.