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Inflammation Impacts Androgen Receptor Signaling in Basal Prostate Stem Cells Through Interleukin 1 Receptor Antagonist [Cut & Tag]

ABSTRACT: 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 utilized a unique transgenic mouse model that mimicschronicnon-bacterial prostatitis in men and investigated the impact of inflammation on androgen receptor (AR) in basal prostate stem cells (bPSC) and their differentiationin vivo. We found that inflammation significantly enhanced AR levels and activity in bPSC. More importantly, we identified interleukin 1 receptor antagonist (IL-1RA) as a crucial regulator of AR in bPSC during inflammation. IL-1RA was one of the top genes upregulated by inflammation, and inhibiting IL-1RA reversed the enhanced AR activity in organoids derived from inflamed bPSC. Additionally, IL-1RA appeared to activate AR by counteracting IL-1a's inhibitory effect. Furthermore, using a lineage tracing model, we observed that inflammation induced 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 uncovered novel mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that may contribute to prostate hyperplasia.

ORGANISM(S): Mus musculus

PROVIDER: GSE269548 | GEO | 2024/06/26

REPOSITORIES: GEO

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Project description:BACKGROUND: Noninvasive methods for the early identify diagnosis of prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa) are current clinical challenges.METHODS: The serum metabolites of 20 healthy individuals and patients with prostatitis, BPH, or PCa were identified using untargeted liquid chromatography-mass spectrometry (LC-MS).RESULTS: Organic acid metabolites had good sensitivity and specificity in differentiating prostatitis, BPH, and PCa. In addition, targeted LC-MS was used to verify the organic acid metabolites in the serum of a validation cohort. Three diagnostic models identified patients with PROSTATITIS: phenyllactic acid (area under the curve [AUC]=0.773), pyroglutamic acid (AUC=0.725), and pantothenic acid (AUC=0.721). Three diagnostic models identified BPH: citric acid (AUC=0.859), malic acid (AUC=0.820), and D-glucuronic acid (AUC=0.810). Four diagnostic models identified PCa: 3-hydroxy-3-methylglutaric acid (AUC=0.804), citric acid (AUC=0.918), malic acid (AUC=0.862), and phenyllactic acid (AUC=0.713). Two diagnostic models distinguished BPH from PCa: phenyllactic acid (AUC=0.769) and pyroglutamic acid (AUC=0.761). Three diagnostic models distinguished benign BPH from PROSTATITIS: citric acid (AUC=0.842), ethylmalonic acid (AUC=0.814), and hippuric acid (AUC=0.733). Six diagnostic models distinguished BPH from prostatitis: citric acid (AUC=0.926), pyroglutamic acid (AUC=0.864), phenyllactic acid (AUC=0.850), ethylmalonic acid (AUC=0.843), 3-hydroxy-3-methylglutaric acid (AUC=0.817), and hippuric acid (AUC=0.791). Three diagnostic models distinguished PCa patients with PROSTATITISA < 4.0 ng/mL from those with PSA > 4.0 ng/mL: 5-hydromethyl-2-furoic acid (AUC=0.749), ethylmalonic acid (A UC=0.750), and pyroglutamic acid (AUC=0.929).CONCLUSIONS: These results suggest that serum organic acid metabolites can be used as biomarkers to differentiate prostatitis, BPH, and PCa. Untargeted assay is reported in the current study MTBLS6039.Targeted organic acid assay is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6038' rel='noopener noreferrer' target='_blank'>MTBLS6038</a>.

Project description:BACKGROUND: Noninvasive methods for the early identify diagnosis of prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are current clinical challenges.METHODS: The serum metabolites of 20 healthy individuals and patients with prostatitis, BPH, or PCa were identified using untargeted liquid chromatography-mass spectrometry (LC-MS).RESULTS: Organic acid metabolites had good sensitivity and specificity in differentiating prostatitis, BPH, and PCa. In addition, targeted LC-MS was used to verify the organic acid metabolites in the serum of a validation cohort. Three diagnostic models identified patients with PROSTATITIS: phenyllactic acid (area under the curve [AUC]=0.773), pyroglutamic acid (AUC=0.725), and pantothenic acid (AUC=0.721). Three diagnostic models identified BPH: citric acid (AUC=0.859), malic acid (AUC=0.820), and D[1]glucuronic acid (AUC=0.810). Four diagnostic models identified PCa: 3-hydroxy-3-methylglutaric acid (AUC=0.804), citric acid (AUC=0.918), malic acid (AUC=0.862), and phenyllactic acid (AUC=0.713). Two diagnostic models distinguished BPH from PCa: phenyllactic acid (AUC=0.769) and pyroglutamic acid (AUC=0.761). Three diagnostic models distinguished benign BPH from PROSTATITIS: citric acid (AUC=0.842), ethylmalonic acid (AUC=0.814), and hippuric acid (AUC=0.733). Six diagnostic models distinguished BPH from prostatitis: citric acid (AUC=0.926), pyroglutamic acid (AUC=0.864), phenyllactic acid (AUC=0.850), ethylmalonic acid (AUC=0.843), 3-hydroxy- 3-methylglutaric acid (AUC=0.817), and hippuric acid (AUC=0.791). Three diagnostic models distinguished PCa patients with PROSTATITISA < 4.0 ng/mL from those with PSA > 4.0 ng/mL: 5-hydromethyl-2-furoic acid (AUC=0.749), ethylmalonic acid (A UC=0.750), and pyroglutamic acid (AUC=0.929).CONCLUSIONS: These results suggest that serum organic acid metabolites can be used as biomarkers to differentiate prostatitis, BPH, and PCa. Targeted organic acid assay is reported in the current study MTBLS6038.Untargeted assay is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS6039' rel='noopener noreferrer' target='_blank'>MTBLS6039</a>.

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Inflammation Impacts Androgen Receptor Signaling in Basal Prostate Stem Cells Through Interleukin 1 Receptor Antagonist [Cut & Tag]

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