Inflammation impacts androgen receptor signaling in basal prostate stem cells through interleukin 1 receptor antagonist
Chronic prostate inflammation in patients with benign prostate hyperplasia (BPH) correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms remain unclear. In this study, we utilize a unique transgenic mouse model that mimics chronic non-bacterial prostatitis in men and investigate the impact of inflammation on androgen receptor (AR) in basal prostate stem cells (bPSC) and their differentiation in vivo. We find that inflammation significantly enhances AR levels and activity in bPSC. More importantly, we identify interleukin 1 receptor antagonist (IL-1RA) as a crucial regulator of AR in bPSC during inflammation. IL-1RA is one of the top molecules upregulated by inflammation, and inhibiting IL-1RA reverses the enhanced AR activity in organoids derived from inflamed bPSC. Additionally, IL-1RA appears to activate AR by counteracting IL-1α's inhibitory effect. Furthermore, using a lineage tracing model, we observe that inflammation induces bPSC proliferation and differentiation into luminal cells even under castrate conditions, indicating that AR activation driven by inflammation is sufficient to promote bPSC proliferation and differentiation. Taken together, our study uncovers mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that may contribute to prostate hyperplasia.
Authors
- Faye Zheng
- Meaghan M. Broman (ORCID: https://orcid.org/0000-0001-5473-1616)
- Bingyu Yan
- Liang Wang (ORCID: https://orcid.org/0000-0002-4052-1316)
- Nadia A. Lanman (ORCID: https://orcid.org/0000-0002-1819-7070)
- Scott A. Crist (ORCID: https://orcid.org/0000-0001-7431-2398)
- Shyaman Jayasundara (ORCID: https://orcid.org/0000-0003-0522-3353)
- Majid Kazemian (ORCID: https://orcid.org/0000-0001-7080-8820)
- Hsing‐Hui Wang (ORCID: https://orcid.org/0000-0003-3283-9583)
- Saeed M. Alqahtani (ORCID: https://orcid.org/0000-0001-9669-2408)
- Robert E. Braun (ORCID: https://orcid.org/0000-0003-3856-9465)
- Paula O. Cooper (ORCID: https://orcid.org/0000-0001-9201-1855)
- Subhransu S. Sahoo (ORCID: https://orcid.org/0000-0003-2946-0484)
- Timothy L. Ratliff (ORCID: https://orcid.org/0000-0003-4221-5416)
- Gregory M. Cresswell (ORCID: https://orcid.org/0000-0003-0616-0366)
- Gada D. Awdalkreem
- Travis J. Jerde
- Liang Cheng (ORCID: https://orcid.org/0000-0001-6049-5293)
- Jiang Yang (ORCID: https://orcid.org/0000-0002-2363-4810)
- R. W. Doerge
- Emery Goossens
Institutions
- University of North Carolina at Chapel Hill (US)
- Rensselaer Polytechnic Institute (US)
- George Washington University (US)
- Purdue University West Lafayette (US)
- Brown University (US)
- Fraternal Order of Eagles (US)
- Tracer Technologies (United States) (US)
- Jackson Laboratory (US)
- Purdue University Institute for Cancer Research
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-10-25
- DOI
- https://doi.org/10.1038/s42003-024-07071-y
- Citations
- 5
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- Walther Cancer Foundation
- Purdue University
- National Institutes of Health
- National Center for Advancing Translational Sciences