{"doi":"10.1002/pros.24081","title":"Neuropeptide Y nerve paracrine regulation of prostate cancer oncogenesis and therapy resistance","abstract":"BACKGROUND: Nerves are key factors in prostate cancer (PCa) progression. Here, we propose that neuropeptide Y (NPY) nerves are key regulators of cancer-nerve interaction. METHODS: We used in vitro models for NPY inhibition studies and subsequent metabolomics, apoptotic and migration assays, and nuclear transcription factor-κB (NF-κB) translocation studies. Human naïve and radiated PCa tissues were used for NPY nerve density biomarker studies. Tissues derived from a Botox denervation clinical trial were used to corroborate metabolomic changes in humans. RESULTS: Cancer cells increase NPY positive nerves in vitro and in preneoplastic human tissues. NPY-specific inhibition resulted in increased cancer apoptosis, decreased motility, and energetic metabolic pathway changes. A comparison of metabolomic response in NPY-inhibited cells with the transcriptome response in human PCa patients treated with Botox showed shared 13 pathways, including the tricarboxylic acid cycle. We identified that NF-κB is a potential NPY downstream mediator. Using in vitro models and tissues derived from a previous human chemical denervation study, we show that Botox specifically, but not exclusively, inhibits NPY in cancer. Quantification of NPY nerves is independently predictive of PCa-specific death. Finally, NPY nerves might be involved in radiation therapy (RT) resistance, as radiation-induced apoptosis is reduced when PCa cells are cocultured with dorsal root ganglia/nerves and NPY positive nerves are increased in prostates of patients that failed RT. CONCLUSION: These data suggest that targeting the NPY neural microenvironment may represent a therapeutic approach for the treatment of PCa and resistance through the regulation of multiple oncogenic mechanisms.","journal":"The Prostate","year":2020,"id":63625,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":43,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.966,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":293012,"name":"MinJae Lee","orcid":"0000-0002-4329-506X","position":1,"is_corresponding":false},{"id":336721,"name":"Yan Gao","orcid":"0000-0003-2937-7429","position":2,"is_corresponding":false},{"id":338273,"name":"Ping Bu","orcid":null,"position":3,"is_corresponding":false},{"id":338274,"name":"Christian Coarfa","orcid":null,"position":4,"is_corresponding":false},{"id":336722,"name":"Brian J. Miles","orcid":"0000-0001-7927-9873","position":5,"is_corresponding":false},{"id":298830,"name":"Arun Sreekumar","orcid":"0000-0003-1582-3774","position":6,"is_corresponding":false},{"id":13376,"name":"Chad J. Creighton","orcid":"0000-0002-6090-703X","position":7,"is_corresponding":false},{"id":336723,"name":"Gustavo Ayala","orcid":"0000-0002-5288-0244","position":8,"is_corresponding":false},{"id":336720,"name":"Yi Ding","orcid":"0000-0001-7748-9914","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T21:11:24.000992Z","pmid":"33022812","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}