Interleukin-6 Regulates Androgen Synthesis in Prostate Cancer Cells

Abstract

Purpose: The standard systemic treatment for prostate cancer patients is androgen deprivation therapy. Although serum testosterone concentrations were significantly reduced after androgen deprivation therapy, levels of intraprostatic androgens are reproducibly measured at concentrations sufficient to activate androgen receptor and stimulate tumor growth, suggesting that prostate cancer cells may survive androgen deprivation therapies by increasing intracrine androgen synthesis within the prostate. However, factors that regulate de novo intracrine androgen synthesis have not been identified. Interleukin-6 (IL-6) has been implicated in the modulation of androgen receptor activation and growth and differentiation in prostate cancer. In this study, we investigate whether IL-6 regulates intraprostatic androgen synthesis in prostate cancer cells. Experimental Design: Quantitative reverse transcription-PCR and Western blotting were done to detect expression levels of steroidogenic enzymes. AKR1C3 promoter reporter was constructed and analyzed for IL-6-mediated AKR1C3 transcriptional activity. IL-6-mediated signaling was knocked down using small interfering RNA specific to IL-6 receptor and gp130, and the effect on AKR1C3 expression was examined. Intraprostatic androgen levels in prostate cancer cells in culture and in tumors were measured by an enzyme immunoassay (Testosterone EIA kit). Results: We found that IL-6 increases the expression of genes encoding many steroidogenic enzymes, including HSD3B2 and AKR1C3, involved in androgen biosynthesis. Down-regulation of IL-6 receptor and gp130 expression using specific small interfering RNA abolished IL-6-mediated AKR1C3 expression, suggesting that IL-6 signaling is responsible for AKR1C3 expression. IL-6 increases AKR1C3 promoter activity, indicating that the increase in IL-6-mediated AKR1C3 expression is in part at the transcriptional level. Treatment of IL-6 increased testosterone level in LNCaP cells. The tumor testosterone levels were detected at 378 pg/g in tumors generated from IL-6-overexpressing LNCaP-IL6 + cells inoculated orthotopically into the prostates of castrated male nude mice. Conclusions: These results suggest that IL-6 increases levels of intracrine androgens through enhanced expression of genes mediating androgen metabolism in prostate cancer cells.

Molecular Chemotherapy and Chemotherapy: A New Front against Late-Stage Hormone-Refractory Prostate Cancer

“…We focused on Th2 cytokines only because, previously, we observed that changes in Th2, and not Th1, cytokines better indicated effects on tumor burden/ response to therapy. A panel of Th2 cytokines, MCP-1, IL-4, IL-6, and IL-10 that are implicated in prostate cancer progression and pathology were selected (27)(28)(29)(30)(31)(32)(33)(34). Sera analyses showed a reduction in all mice given the combination regimen (Fig.…”

“…Although serum cytokines levels typically reflect the specific immune status of the host, a shift of the cytokine balance to Th2 has been shown to be associated with cancer progression (44,45). On this premise and to further test our previous finding that Th2 cytokines are a reliable predictor of tumor burden and treatment efficacy, we undertook an analysis of a panel of Th2 cytokines, MCP-1, IL-4, IL-10, and IL-6, that are implicated in prostate cancer progression, including development of androgen-refractory phenotype (27,(29)(30)(31)(46)(47)(48)(49)(50). In agreement with our previous findings (22), the reduced levels of serum Th2 cytokines, MCP-1, IL-4, and IL6 profiles ( Fig.…”

Redox-Mediated and Ionizing-Radiation-Induced Inflammatory Mediators in Prostate Cancer Development and Treatment

“…Most clinical data support the biological role of the IL-6 pathway in prostate cancer, especially in an advanced castration-resistant prostate cancer patient where the significance of the IL-6 pathway is mediated by crosstalk between IL-6 and the AR pathway (9). Under androgen deprivation conditions, IL-6 is able to promote intracellular synthesis of androgens in the prostate (36), resulting in AR activation and upregulation of ARtargeted prostate specific antigen (PSA) expression, via STAT3 and MAPK signaling pathways (9), as well as an androgen enhancer region within the human PSA promoter (184).…”

Sex steroids in the tumor microenvironment and prostate cancer progression

“…PSA values were also correlated with all hormone values at 6 months, but not at baseline (Takizawa et al 2010). IL-6, which is associated with advanced PCa, has also been linked with serum testosterone and DHEA among men treated with ADT (Chun et al 2009, Komatsu et al 2012. Steroidogenesis is higher in metastatic lesions, and this may also be stimulated by osteoclasts or extravesicle transport of CYP17 (Locke et al 2009, Jernberg et al 2013, Hagberg Thulin et al 2016.…”