{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T08:48:13Z","timestamp":1788684493441,"version":"build-2803163510"},"reference-count":251,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ASPIRE Precision Medicine Research Institute Abu Dhabi","award":["(VRI-20\u201310)"],"award-info":[{"award-number":["(VRI-20\u201310)"]}]},{"DOI":"10.13039\/100016714","name":"University of Sharjah","doi-asserted-by":"publisher","award":["23010902146"],"award-info":[{"award-number":["23010902146"]}],"id":[{"id":"10.13039\/100016714","id-type":"DOI","asserted-by":"publisher"}]},{"award":["23010902146"],"award-info":[{"award-number":["23010902146"]}],"id":[{"id":"https:\/\/ror.org\/00engpz63","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Prostate cancer (PC) progression is increasingly recognized as a dynamic, inflammation-driven process in which chronic immune dysregulation contributes to disease aggressiveness and therapeutic resistance. Among inflammatory signaling pathways, nuclear factor kappa B (NF-\u03baB) has been consistently implicated in prostate tumorigenesis, castration resistance, and apoptosis resistance. However, despite the extensive literature on NF-\u03baB biology, the mechanisms by which its dysregulation is sustained and functionally shaped during PC progression remain incompletely understood. This review synthesizes current evidence on prostate cancer-specific NF-\u03baB signaling, with an emphasis on stage-dependent activation, molecular regulation within the tumor microenvironment, and downstream transcriptional programs linked to survival and treatment resistance. Particular attention is given to the regulatory role of B-cell lymphoma-3 (BCL-3), an atypical nuclear I\u03baB protein, and its potential interplay with B-cell lymphoma-2 (BCL-2), a well-established NF-\u03baB-regulated anti-apoptotic factor in PC. Available clinical, molecular, and transcriptomic data support constitutive NF-\u03baB activation across multiple stages of PC, particularly in advanced and castration-resistant disease. Although BCL-2 overexpression is well documented as a mediator of apoptosis resistance in PC, evidence directly linking BCL-3 to BCL-2 regulation in this disease remains limited. Data from other malignancies suggest that BCL-3 can modulate NF-\u03baB transcriptional output and enhance BCL-2 expression; however, prostate-specific mechanistic validation is lacking. We propose a testable, hypothesis-driven model in which BCL-3 may function as a context-dependent regulator of NF-\u03baB-mediated survival signaling in PC, potentially influencing BCL-2 expression and therapeutic resistance. However, this relationship remains speculative and is not yet supported by direct mechanistic evidence in PC. By distinguishing between established evidence and inferred mechanisms, this review highlights critical knowledge gaps and outlines experimental strategies to clarify the functional relevance of the BCL-3\/BCL-2 axis. Improved understanding of NF-\u03baB regulatory dynamics may inform the development of more precise, stage-adapted therapeutic strategies for advanced PC.<\/jats:p>","DOI":"10.3390\/cancers18081227","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T10:19:14Z","timestamp":1776075554000},"page":"1227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["NF-\u03baB Signaling in Prostate Cancer Progression: Inflammatory Mediators, Survival Pathways, and Regulatory Axes"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4380-5445","authenticated-orcid":false,"given":"Ranyah","family":"Al-Hakm","sequence":"first","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2301-0899","authenticated-orcid":false,"given":"Alaa Muayad","family":"Altaie","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Center of Excellence for Precision Medicine, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anania","family":"Boghossian","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5158-4590","authenticated-orcid":false,"given":"Riyad","family":"Bendardaf","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Oncology Unit, University Hospital Sharjah, Sharjah P.O. Box 72772, United Arab Emirates"},{"name":"Center of Excellence for Cancer Research, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5259-327X","authenticated-orcid":false,"given":"Iman M.","family":"Talaat","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Pathology Department, Faculty of Medicine, Alexandria University, Alexandria P.O. Box 21131, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-0868","authenticated-orcid":false,"given":"Rifat","family":"Hamoudi","sequence":"additional","affiliation":[{"name":"Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Center of Excellence for Precision Medicine, Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Biomedically Informed Artificial Intelligence Laboratory (BIMAI-Lab), University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"ASPIRE Precision Medicine Research Institute Abu Dhabi, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Division of Surgery and Interventional Science, University College London, London NW3 2PS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.eururo.2024.11.013","article-title":"Recent Patterns and Trends in Global Prostate Cancer Incidence and Mortality: An Update","volume":"87","author":"Schafer","year":"2025","journal-title":"Eur. Urol."},{"key":"ref_2","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","unstructured":"Bott, S.R., and Ng, K.L. (2021). Prostate Cancer, Exon Publications. 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