Androgens2016 Poster Presentations (1) (42 abstracts)
The bi-directional interaction of AR and IL6 signalling in the response to enzalutamide in prostate cancer cells
Florian Handle 1 , Holger HH Erb 1, , Birgit Luef 1 , Julia Hoefer 1 , Dimo Dietrich 3 , Walther Parson 4, , Glen Kristiansen 3 , Frédéric R Santer 1, & Zoran Culig 1,
1Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria; 2Yorkshire Cancer Research Unit, University of York, York, UK; 3Institute of Pathology, University Hospital Bonn, Bonn, Germany; 4Institute of Legal Medicine, Medical University of Innsbruck, Innsbruck, Austria; 5Forensic Science Program, The Pennsylvania State University, University Park, Pennsylvania, USA; †Joint senior authors.
Chronic inflammation and high expression of pro-inflammatory cytokines, such as Interleukin-6 (IL6), are well-known risk factors for prostate cancer (PCa). IL6 is known to activate the androgen receptor (AR) and has been implicated in development of castration resistance. Therefore, we wanted to investigate the interaction of AR and IL6 signalling and the effect on anti-androgen treatment. We could confirm IL6 mediated activation of the AR on 3 AR target genes in presence of R1881 by qPCR in LNCaP (P<0.001). In contrast to previous publications we could not detect AR activation in absence of androgens. Mechanistically, IL6 did not change AR protein expression nor nuclear localization, which suggests that the transactivation potential of the AR is enhanced. Interestingly, anti-androgen treatment of LNCaP and DuCaP cells led to increased IL6 signalling and an upregulation of the IL6 induced negative feedback-regulator SOCS3. This effect could be linked to a direct AR mediated suppression of IL6ST and JAK1, two key components of the IL6 receptor complex. Normally, induction of SOCS3 expression would counteract the increase in IL6 activity, but we found that the promoter region of SOCS3 is hypermethylated in more than 85% of PCa patients (n=269), which has been linked to reduced mRNA expression previously. Functionally, SOCS3 knock-down was able to abrogate the effect of enzalutamide on PSA expression in presence of IL6. In conclusion, we could show a bi-directional interaction of the AR and IL6 pathways and this effect could play an important role during anti-androgen treatment, especially under low SOCS3 conditions.
Funding: This work was funded by the Austrian Science Fund (FWF) grants P24428 and W1101-B12 (to Z Culig) and by the Austrian Cancer Society/Tirol (to F Handle).
Presenting author: Florian Handle, Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Anichstr 35, A-6020, Innsbruck, Austria. Email: [email protected].
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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