{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:47:06Z","timestamp":1785764826711,"version":"3.56.0"},"reference-count":66,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Vranos Family Foundation","award":["FD135390"],"award-info":[{"award-number":["FD135390"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Long-established prostate cancer cell lines provide limited insight into how contemporary early prostate cancer evolves into drug-resistant and neuroendocrine-like refractory disease. Patient-derived three-dimensional (3D) ex vivo models may better preserve this transition. Here, we found that 8 of 10 magnetic resonance imaging-guided biopsy specimens from patients with early-stage prostate cancer generated sustained 3D tumor spheroid cultures. After 12 weeks of enzalutamide selection, only one patient-derived culture acquired a resistant phenotype with treatment-emergent neuroendocrine prostate cancer (t-NEPC)-like features, including increased chromogranin A (CgA) and synaptophysin (SYP); reduced androgen receptor (AR), prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA); and conversion from compact spheroids into irregular resistant aggregates. During this transition, WD repeat and SOCS box-containing protein 1 (WSB1) increased, whereas PSMA progressively decreased. WSB1 silencing restored PSMA, AR, and PSA expression and reduced neuroendocrine-associated features. A similar WSB1 dependency was observed in enzalutamide-resistant LNCaP cells, the castration-resistant prostate cancer model 22Rv1, and the neuroendocrine\/small-cell prostate cancer model NCI-H660. Mechanistically, WSB1 functioned as a SOCS box-dependent E3 ubiquitin ligase adaptor that promoted PSMA ubiquitination and degradation. SOCS box deletion or T380A mutation impaired this process, while Aurora kinase A (AURKA) inhibition reduced WSB1-dependent PSMA ubiquitination. WSB1 depletion, AURKA inhibition with alisertib, and combined AURKA inhibition with EZH2 suppression reduced resistant aggregate growth and increased apoptosis-associated markers in patient-derived enzalutamide-resistant neuroendocrine-like spheroids and related models. These findings nominate the AURKA\u2013WSB1\u2013PSMA axis as a therapeutic vulnerability in refractory prostate cancer.<\/jats:p>","DOI":"10.3390\/ijms27156899","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6899","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["WSB1-Mediated PSMA Ubiquitination Promotes Enzalutamide-Induced Neuroendocrine-like Transition in Patient-Derived Prostate Cancer Spheroids"],"prefix":"10.3390","volume":"27","author":[{"given":"Dawa","family":"Jung","sequence":"first","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3892-4754","authenticated-orcid":false,"given":"Ayse Tuba","family":"Kendi","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Woodrum","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Adamo","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8001-6237","authenticated-orcid":false,"given":"Myung-Ho","family":"In","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gokce","family":"Belge Bilgin","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4217-5517","authenticated-orcid":false,"given":"Derek R.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian M.","family":"Horn","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Joo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Ook","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501757, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seon-Young","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501757, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffry L.","family":"Curran","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5612-1667","authenticated-orcid":false,"given":"Val J.","family":"Lowe","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4754-4481","authenticated-orcid":false,"given":"SeungBaek","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","first-page":"12","article-title":"Cancer Statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA A Cancer J. 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