{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T19:42:17Z","timestamp":1772134937000,"version":"3.50.1"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Discov."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Despite the initial efficacy of radiotherapy (RT) in treating prostate adenocarcinoma (PCa), disease progression can lead to the emergence of neuroendocrine prostate cancer (NEPC) - a highly aggressive malignancy for which standard therapies are mostly ineffective. Although oncogenic\n                    <jats:italic>MUC1-C<\/jats:italic>\n                    is a leading driver of NEPC and of PCa lineage plasticity, its putative role in response to RT, including RT-induced neuroendocrine transdifferentiation (tNED), has not been explored. We thus aimed to explore the interplay between androgen receptor (AR) signaling and MUC1 in PCa progression to NEPC. Firstly, using a radioresistant PCa cell line (22Rv1-RR), we demonstrated that epigenetic suppression of AR signaling led to MUC1\/MUC1-C upregulation, which seems to be activated through \u03b3STAT3. MUC1 activation is positively associated with increased expression of neuroendocrine-related markers, including CD56, chromogranin A, synaptophysin, and INSM transcriptional repressor 1 (INSM1). In NEPC tissues and compared to prostate adenocarcinoma, MUC1 was upregulated and negatively correlated with AR, which was suppressed. Finally, proteomic analyses revealed that MUC1 activation upon RT selective pressure led to the acquisition of stemness features, induction of epithelial to mesenchymal transition, and enhancement of basal cell-like traits. Notably, MUC1 knockdown significantly boosted response to RT in both 22Rv1-RR and DU145 cell lines. Moreover, AR-induced overexpression in PC3 cell lines entailed MUC1 downregulation, resulting in attenuated neuroendocrine traits and radioresistance, as well as impaired cell migration and invasion capabilities. Collectively, these results highlight MUC1 as a promising radiosensitization target and may ultimately help overcome therapy resistance and NEPC progression.\n                  <\/jats:p>","DOI":"10.1038\/s41420-025-02597-4","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T16:38:02Z","timestamp":1751560682000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding MUC1 and AR axis in a radiation-induced neuroendocrine prostate cancer cell-subpopulation unveils novel therapeutic targets"],"prefix":"10.1038","volume":"11","author":[{"given":"Catarina","family":"Macedo-Silva","sequence":"first","affiliation":[]},{"given":"\u00c2ngela","family":"Albuquerque-Castro","sequence":"additional","affiliation":[]},{"given":"Iris","family":"Carri\u00e7o","sequence":"additional","affiliation":[]},{"given":"Joana","family":"Lencart","sequence":"additional","affiliation":[]},{"given":"Isa","family":"Carneiro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7312-5387","authenticated-orcid":false,"given":"Lucia","family":"Altucci","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6829-1391","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Lobo","sequence":"additional","affiliation":[]},{"given":"Vera","family":"Miranda-Gon\u00e7alves","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-4666","authenticated-orcid":false,"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4378-0820","authenticated-orcid":false,"given":"Margareta P.","family":"Correia","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"2597_CR1","doi-asserted-by":"publisher","first-page":"778758","DOI":"10.3389\/fendo.2021.778758","volume":"12","author":"J Yao","year":"2021","unstructured":"Yao J, Liu Y, Liang X, Shao J, Zhang Y, Yang J, et al. Neuroendocrine Carcinoma as an Independent Prognostic Factor for Patients With Prostate Cancer: A Population-Based Study. Front Endocrinol (Lausanne). 2021;12:778758.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2597_CR2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.ejca.2019.08.011","volume":"121","author":"V Conteduca","year":"2019","unstructured":"Conteduca V, Oromendia C, Eng KW, Bareja R, Sigouros M, Molina A, et al. Clinical features of neuroendocrine prostate cancer. Eur J Cancer. 2019;121:7\u201318.","journal-title":"Eur J Cancer"},{"key":"2597_CR3","doi-asserted-by":"publisher","first-page":"1405.","DOI":"10.3390\/cancers11101405","volume":"11","author":"GK Patel","year":"2019","unstructured":"Patel GK, Chugh N, Tripathi M. Neuroendocrine Differentiation of Prostate Cancer-An Intriguing Example of Tumor Evolution at Play. Cancers (Basel). 2019;11:1405.","journal-title":"Cancers (Basel)"},{"key":"2597_CR4","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3389\/fonc.2015.00090","volume":"5","author":"CD Hu","year":"2015","unstructured":"Hu CD, Choo R, Huang J. Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure. Front Oncol. 2015;5:90.","journal-title":"Front Oncol"},{"key":"2597_CR5","first-page":"834","volume":"1","author":"X Deng","year":"2011","unstructured":"Deng X, Elzey BD, Poulson JM, Morrison WB, Ko SC, Hahn NM, et al. Ionizing radiation induces neuroendocrine differentiation of prostate cancer cells in vitro, in vivo and in prostate cancer patients. Am J Cancer Res. 2011;1:834\u201344.","journal-title":"Am J Cancer Res"},{"key":"2597_CR6","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.bbcan.2018.06.006","volume":"1870","author":"R Soundararajan","year":"2018","unstructured":"Soundararajan R, Paranjape AN, Maity S, Aparicio A, Mani SA. EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers. Biochim Biophys Acta Rev Cancer. 2018;1870:229\u201338.","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"2597_CR7","doi-asserted-by":"publisher","first-page":"3363.","DOI":"10.3390\/cancers15133363","volume":"15","author":"R Cartes","year":"2023","unstructured":"Cartes R, Karim MU, Tisseverasinghe S, Tolba M, Bahoric B, Anidjar M, et al. Neoadjuvant versus Concurrent Androgen Deprivation Therapy in Localized Prostate Cancer Treated with Radiotherapy: A Systematic Review of the Literature. Cancers (Basel). 2023;15:3363.","journal-title":"Cancers (Basel)"},{"key":"2597_CR8","doi-asserted-by":"publisher","first-page":"865350","DOI":"10.3389\/fonc.2022.865350","volume":"12","author":"J Huang","year":"2022","unstructured":"Huang J, Lin B, Li B. Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective. Front Oncol 2022;12:865350.","journal-title":"Front Oncol"},{"key":"2597_CR9","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1016\/j.eururo.2014.09.049","volume":"67","author":"T Karantanos","year":"2015","unstructured":"Karantanos T, Evans CP, Tombal B, Thompson TC, Montironi R, Isaacs WB. Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. Eur Urol. 2015;67:470\u20139.","journal-title":"Eur Urol"},{"key":"2597_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.canlet.2021.06.006","volume":"518","author":"A Jamroze","year":"2021","unstructured":"Jamroze A, Chatta G, Tang DG. Androgen receptor (AR) heterogeneity in prostate cancer and therapy resistance. Cancer Lett. 2021;518:1\u20139.","journal-title":"Cancer Lett"},{"key":"2597_CR11","doi-asserted-by":"publisher","first-page":"1526.","DOI":"10.3390\/biom13101526","volume":"13","author":"V Camilo","year":"2023","unstructured":"Camilo V, Pacheco MB, Moreira-Silva F, Outeiro-Pinho G, Gaspar VM, Mano JF, et al. Novel Insights on the Role of Epigenetics in Androgen Receptor\u2019s Expression in Prostate Cancer. Biomolecules. 2023;13:1526.","journal-title":"Biomolecules"},{"key":"2597_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14219-6","volume":"11","author":"Y Yasumizu","year":"2020","unstructured":"Yasumizu Y, Rajabi H, Jin C, Hata T, Pitroda S, Long MD, et al. MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer. Nat Commun. 2020;11:338.","journal-title":"Nat Commun"},{"key":"2597_CR13","doi-asserted-by":"publisher","first-page":"811","DOI":"10.7150\/ijbs.79928","volume":"19","author":"Y Yu","year":"2023","unstructured":"Yu Y, Yu J, Ge S, Su Y, Fan X. Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy. Int J Biol Sci. 2023;19:811\u201328.","journal-title":"Int J Biol Sci"},{"key":"2597_CR14","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1080\/21655979.2020.1791590","volume":"11","author":"TQ Huang","year":"2020","unstructured":"Huang TQ, Bi YN, Cui Z, Guan JP, Huang YC. MUC1 confers radioresistance in head and neck squamous cell carcinoma (HNSCC) cells. Bioengineered. 2020;11:769\u201378.","journal-title":"Bioengineered"},{"key":"2597_CR15","first-page":"7571","volume":"14","author":"FT Yi","year":"2017","unstructured":"Yi FT, Lu QP. Mucin 1 promotes radioresistance in hepatocellular carcinoma cells through activation of JAK2\/STAT3 signaling. Oncol Lett. 2017;14:7571\u20136.","journal-title":"Oncol Lett"},{"key":"2597_CR16","doi-asserted-by":"publisher","first-page":"2086","DOI":"10.1038\/sj.bjc.6602232","volume":"91","author":"CF Qu","year":"2004","unstructured":"Qu CF, Li Y, Song YJ, Rizvi SMA, Raja C, Zhang D, et al. MUC1 expression in primary and metastatic pancreatic cancer cells for in vitro treatment by 213Bi-C595 radioimmunoconjugate. Br J Cancer. 2004;91:2086\u201393.","journal-title":"Br J Cancer"},{"key":"2597_CR17","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/s41392-023-01639-6","volume":"8","author":"C Macedo-Silva","year":"2023","unstructured":"Macedo-Silva C, Miranda-Gon\u00e7alves V, Tavares NT, Barros-Silva D, Lencart J, Lobo J, et al. Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling. Signal Transduct Target Ther. 2023;8:395.","journal-title":"Signal Transduct Target Ther"},{"key":"2597_CR18","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1002\/pros.21344","volume":"71","author":"H Rajabi","year":"2011","unstructured":"Rajabi H, Joshi MD, Jin C, Ahmad R, Kufe D. Androgen receptor regulates expression of the MUC1-C oncoprotein in human prostate cancer cells. Prostate. 2011;71:1299\u2013308.","journal-title":"Prostate"},{"key":"2597_CR19","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/j.ecl.2011.05.012","volume":"40","author":"CH Lee","year":"2011","unstructured":"Lee CH, Akin-Olugbade O, Kirschenbaum A. Overview of prostate anatomy, histology, and pathology. Endocrinol Metab Clin North Am. 2011;40:565\u201375.","journal-title":"Endocrinol Metab Clin North Am"},{"key":"2597_CR20","doi-asserted-by":"publisher","first-page":"215","DOI":"10.5114\/jcb.2013.39210","volume":"5","author":"AV Taira","year":"2013","unstructured":"Taira AV, Merrick GS, Butler WM, Galbreath RW, Fiano R, Wallner KE, et al. Time to failure after definitive therapy for prostate cancer: implications for importance of aggressive local treatment. J Contemp Brachytherapy. 2013;5:215\u201321.","journal-title":"J Contemp Brachytherapy"},{"key":"2597_CR21","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1002\/cncr.23161","volume":"112","author":"PK Agarwal","year":"2008","unstructured":"Agarwal PK, Sadetsky N, Konety BR, Resnick MI, Carroll PR. Treatment failure after primary and salvage therapy for prostate cancer: likelihood, patterns of care, and outcomes. Cancer. 2008;112:307\u201314.","journal-title":"Cancer"},{"key":"2597_CR22","doi-asserted-by":"publisher","first-page":"288","DOI":"10.5534\/wjmh.180040","volume":"37","author":"K Fujita","year":"2019","unstructured":"Fujita K, Nonomura N. Role of Androgen Receptor in Prostate Cancer: A Review. World J Mens Health. 2019;37:288\u201395.","journal-title":"World J Mens Health"},{"key":"2597_CR23","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1210\/er.2002-0032","volume":"25","author":"CA Heinlein","year":"2004","unstructured":"Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25:276\u2013308.","journal-title":"Endocr Rev"},{"key":"2597_CR24","doi-asserted-by":"publisher","first-page":"9663","DOI":"10.1158\/0008-5472.CAN-08-2229","volume":"68","author":"X Deng","year":"2008","unstructured":"Deng X, Liu H, Huang J, Cheng L, Keller ET, Parsons SJ, et al. Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: implications for disease progression. Cancer Res. 2008;68:9663\u201370.","journal-title":"Cancer Res"},{"key":"2597_CR25","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1111\/his.14707","volume":"81","author":"A Gopalan","year":"2022","unstructured":"Gopalan A, Al-Ahmadie H, Chen YB, Sarungbam J, Sirintrapun SJ, Tickoo SK, et al. Neuroendocrine differentiation in the setting of prostatic carcinoma: contemporary assessment of a consecutive series. Histopathology. 2022;81:246\u201354.","journal-title":"Histopathology"},{"key":"2597_CR26","doi-asserted-by":"publisher","first-page":"1761","DOI":"10.1002\/pros.20654","volume":"67","author":"A Leiblich","year":"2007","unstructured":"Leiblich A, Cross SS, Catto JW, Pesce G, Hamdy FC, Rehman I. Human prostate cancer cells express neuroendocrine cell markers PGP 9.5 and chromogranin A. Prostate. 2007;67:1761\u20139.","journal-title":"Prostate"},{"key":"2597_CR27","doi-asserted-by":"publisher","first-page":"3178","DOI":"10.1038\/s41598-024-53549-4","volume":"14","author":"M Bose","year":"2024","unstructured":"Bose M, Sanders A, Handa A, Vora A, Cardona MR, Brouwer C, et al. Molecular crosstalk between MUC1 and STAT3 influences the anti-proliferative effect of Napabucasin in epithelial cancers. Sci Rep. 2024;14:3178.","journal-title":"Sci Rep."},{"key":"2597_CR28","doi-asserted-by":"publisher","first-page":"ra9","DOI":"10.1126\/scisignal.2001426","volume":"4","author":"R Ahmad","year":"2011","unstructured":"Ahmad R, Rajabi H, Kosugi M, Joshi MD, Alam M, Vasir B, et al. MUC1-C oncoprotein promotes STAT3 activation in an autoinductive regulatory loop. Sci Signal. 2011;4:ra9.","journal-title":"Sci Signal"},{"key":"2597_CR29","first-page":"337","volume":"35","author":"J Gao","year":"2009","unstructured":"Gao J, McConnell MJ, Yu B, Li J, Balko JM, Black EP, et al. MUC1 is a downstream target of STAT3 and regulates lung cancer cell survival and invasion. Int J Oncol. 2009;35:337\u201345.","journal-title":"Int J Oncol"},{"key":"2597_CR30","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2020.100899","volume":"14","author":"JS Wu","year":"2021","unstructured":"Wu JS, Jiang J, Chen BJ, Wang K, Tang YL, Liang XH. Plasticity of cancer cell invasion: Patterns and mechanisms. Transl Oncol. 2021;14:100899.","journal-title":"Transl Oncol"},{"key":"2597_CR31","doi-asserted-by":"publisher","first-page":"14406","DOI":"10.1073\/pnas.1519151112","volume":"112","author":"L Ellis","year":"2015","unstructured":"Ellis L, Loda M. Advanced neuroendocrine prostate tumors regress to stemness. Proc Natl Acad Sci USA. 2015;112:14406\u20137.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2597_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-03279-y","volume":"11","author":"C Macedo-Silva","year":"2020","unstructured":"Macedo-Silva C, Miranda-Gon\u00e7alves V, Lameirinhas A, Lencart J, Pereira A, Lobo J, et al. JmjC-KDMs KDM3A and KDM6B modulate radioresistance under hypoxic conditions in esophageal squamous cell carcinoma. Cell Death Dis. 2020;11:1068.","journal-title":"Cell Death Dis"}],"container-title":["Cell Death Discovery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41420-025-02597-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-025-02597-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41420-025-02597-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T16:38:03Z","timestamp":1751560683000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41420-025-02597-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,3]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2597"],"URL":"https:\/\/doi.org\/10.1038\/s41420-025-02597-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-5614729\/v1","asserted-by":"object"}]},"ISSN":["2058-7716"],"issn-type":[{"value":"2058-7716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,3]]},"assertion":[{"value":"15 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 June 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 June 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 July 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study used PCa biopsy specimens as FFPE tissue samples. For that purpose, this study was approved by the institutional review board (Comiss\u00e3o de \u00c9tica para a Sa\u00fade) of IPO Porto, Portugal (CES-238\/020). All procedures involving human samples were in accordance with the ethical standards about informed consent of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All methods were performed in accordance with the relevant guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"306"}}