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Here, we propose that neuropeptide Y (NPY) nerves are key regulators of cancer\u2013nerve interaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used in vitro models for NPY inhibition studies and subsequent metabolomics, apoptotic and migration assays, and nuclear transcription factor\u2010\u03baB (NF\u2010\u03baB)\u00a0translocation studies. Human na\u00efve 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cancer cells increase NPY positive nerves in vitro and in preneoplastic human tissues. NPY\u2010specific inhibition resulted in increased cancer apoptosis, decreased motility, and energetic metabolic pathway changes. A comparison of metabolomic response in NPY\u2010inhibited cells with the transcriptome response in human PCa patients treated with Botox showed shared 13 pathways, including the tricarboxylic acid\u00a0cycle. We identified that NF\u2010\u03baB\u00a0is 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\u2010specific death. Finally, NPY nerves might be involved in radiation therapy (RT) resistance, as radiation\u2010induced 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.24081","type":"journal-article","created":{"date-parts":[[2020,10,6]],"date-time":"2020-10-06T22:40:29Z","timestamp":1602024029000},"page":"58-71","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Neuropeptide Y nerve paracrine regulation of prostate cancer oncogenesis and therapy resistance"],"prefix":"10.1002","volume":"81","author":[{"given":"Yi","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, McGovern School of Medicine University of Texas Health Sciences Center Medical School Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MinJae","family":"Lee","sequence":"additional","affiliation":[{"name":"Biostatistics, Epidemiology, and Research Design (BERD) Core, Department of Internal Medicine University of Texas Health Sciences Center Medical School Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, McGovern School of Medicine University of Texas Health Sciences Center Medical School Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Bu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, McGovern School of Medicine University of Texas Health Sciences Center Medical School Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Coarfa","sequence":"additional","affiliation":[{"name":"Department of Molecular &amp; Cell Biology Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Miles","sequence":"additional","affiliation":[{"name":"Department of Urology The Methodist Hospital Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun","family":"Sreekumar","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, McGovern School of Medicine University of Texas Health Sciences Center Medical School Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad J.","family":"Creighton","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Dan L. 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