ArticleFrontiers in pharmacology2026
SLPI is associated with AR-regulated epithelial adaptation and enzalutamide sensitivity in castration-resistant prostate cancer.
Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Castration-resistant prostate cancer (CRPC) develops through tumor-cell plasticity, androgen receptor (AR) pathway rewiring, and immune/stromal changes under therapeutic pressure. Because metastatic CRPC often responds incompletely to immunotherapy and AR-directed treatment, cell-resolved analyses may help place putative drug-response factors within their tissue context. We examined whether secretory leukocyte protease inhibitor (SLPI), an epithelial secreted factor with immunoregulatory functions, is related to epithelial-state changes and enzalutamide response. Methods: Public single-cell RNA-sequencing data from localized prostate cancer and metastatic CRPC (GSE274229) were analyzed using Seurat-based preprocessing, cell-type annotation, UCell pathway/state scoring, CellChat ligand-receptor inference, CopyKAT malignant-cell inference, Monocle2 trajectory analysis, hdWGCNA network analysis, and TCGA-PRAD clinical association analysis. SLPI was evaluated in 22Rv1 and C4-2 prostate cancer models using stable overexpression, qRT-PCR, proliferation, colony formation, migration, AR-pathway modulation, enzalutamide dose-response, and Annexin V/PI apoptosis assays. Results: Progression to mCRPC was accompanied by altered epithelial-immune/stromal communication and shifts in inflammatory, extracellular-matrix, growth-factor, and immune-regulatory signaling. Putative malignant epithelial populations showed reduced AR-dependency and luminal-identity scores together with increased stress-adaptation and plasticity programs. Network and clinical association analyses highlighted SLPI as a progression-related epithelial factor with outcome relevance. Conclusion: These findings place SLPI at the intersection of AR-pathway state, epithelial adaptation, immune-context changes, and enzalutamide sensitivity in CRPC. SLPI may represent a therapy-response-associated epithelial factor in prostate cancer, but further protein-level, loss-of-function,
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