{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:13:36Z","timestamp":1787022816769,"version":"build-2736575974"},"reference-count":35,"publisher":"Bioscientifica","issue":"7","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Somatic mutations in the gene encoding splicing factor 3B subunit 1 (SF3B1), a key component of the splicing machinery, have been described in patients with PRL-secreting pituitary neuroendocrine tumors (PRL-PitNETs) and associated with aggressiveness and resistance to pharmacological therapy with dopamine agonists (DAs). Dopamine receptor type 2 (DRD2) represents the main target for PRL-PitNET treatment with DAs, even if about 10% of patients is resistant. The aims of the study were to i) test the effects of SF3B1 inhibitor pladienolide B in tumoral lactotroph cells expressing wild-type or mutated SF3B1R625H and ii) investigate the impact of SF3B1 on tumoral cells\u2019 responsiveness to DRD2 agonist cabergoline. Pladienolide B treatment reduced cell proliferation (\u221245.1(15.3)%, P &amp;lt; 0.001) and PRL secretion (\u221219.25(35.1)%, P &amp;lt; 0.05) and increased apoptosis (+2.4(2.5)-fold, P &amp;lt; 0.05) in rat tumoral MMQ cells. The antimitotic, proapoptotic, and antisecretory effects of pladienolide B were maintained in primary cultured cells from both resistant and responsive PRL-PitNETs. SF3B1R625H overexpression increased tumoral lactotroph proliferation and migration. Moreover, the antimitotic efficacy of pladienolide B, but not of cabergoline, was maintained in MMQ cells transfected with SF3B1R625H. Cabergoline effects on cell proliferation, AKT activation, cyclin D3, and p27 were abolished in MMQ cells silenced for SF3B1. Accordingly, SF3B1R625H overexpression and SF3B1 silencing reduced DRD2 expression at both protein and transcript levels, an effect reverted by nonsense-mediated decay inhibitor NMDI14. In conclusion, we demonstrated a relevant role of SF3B1 in PRL-PitNETs. Indeed, SF3B1 inhibitor pladienolide B exerted antitumoral actions in PRL-PitNET cells bearing wild-type or mutated SF3B1. Moreover, both SF3B1R625H overexpression and SF3B1 genetic silencing reduced DRD2 expression and signaling.<\/jats:p>","DOI":"10.1530\/erc-25-0527","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T12:39:21Z","timestamp":1781872761000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":1,"title":["Characterization of SF3B1 role in prolactin-secreting pituitary tumors"],"prefix":"10.1530","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2758-5841","authenticated-orcid":true,"given":"Federica","family":"Mangili","sequence":"first","affiliation":[{"name":"Endocrinology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico 1 , ,","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Barbieri","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, Department of Excellence 2023\u20132027, University of Milan 2 , ,","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genesio","family":"Di Muro","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, Department of Excellence 2023\u20132027, University of Milan 2 , ,","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, Department of Excellence 2023\u20132027, University of Milan 2 , ,","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6636-2619","authenticated-orcid":true,"given":"Donatella","family":"Treppiedi","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico 1 , ,","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Locatelli","sequence":"additional","affiliation":[{"name":"Neurosurgery Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico 3 , ,","place":["Milan, Italy"]},{"name":"Department of Pathophysiology and Transplantation, University of Milan 4 , ,","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea G","family":"Lania","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University 5 , ,","place":["Pieve Emanuele, Italy"]},{"name":"Endocrinology and Diabetology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital 6 , ,","place":["Rozzano, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4101-9432","authenticated-orcid":true,"given":"M\u00e1rta","family":"Korbonits","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London 7 , ,","place":["London, UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4424-7895","authenticated-orcid":true,"given":"Erika","family":"Peverelli","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico 1 , ,","place":["Milan, Italy"]},{"name":"Department of Clinical Sciences and Community Health, Department of Excellence 2023\u20132027, University of Milan 2 , ,","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Mantovani","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico 1 , ,","place":["Milan, Italy"]},{"name":"Department of Clinical Sciences and Community Health, Department of Excellence 2023\u20132027, University of Milan 2 , ,","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"2026071706064931100_bib1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1159\/000495775","article-title":"Management of dopamine agonist-resistant prolactinoma","volume":"109","author":"Maiter","year":"2019","journal-title":"Neuroendocrinology"},{"key":"2026071706064931100_bib2","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/s41574-021-00514-0","article-title":"Drug resistance in pituitary tumors: from cell membrane to intracellular signaling","volume":"17","author":"Peverelli","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"2026071706064931100_bib3","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1038\/s41467-020-16052-8","article-title":"Somatic SF3B1 hotspot mutation in prolactinomas","volume":"11","author":"Li","year":"2020","journal-title":"Nat Commun"},{"key":"2026071706064931100_bib4","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13046-022-02245-0","article-title":"The SF3B1R625H mutation promotes prolactinoma tumour progression through aberrant splicing of DLG1","volume":"41","author":"Guo","year":"2022","journal-title":"J Exp Clin Cancer Res"},{"key":"2026071706064931100_bib5","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1093\/ejendo\/lvad114","article-title":"Prevalence and clinical correlations of SF3B1 variants in lactotroph tumors","volume":"189","author":"Simon","year":"2023","journal-title":"Eur J Endocrinol"},{"key":"2026071706064931100_bib6","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1093\/ejendo\/lvad148","article-title":"Genetic testing in prolactinomas: a cohort study","volume":"189","author":"Boukerrouni","year":"2023","journal-title":"Eur J Endocrinol"},{"key":"2026071706064931100_bib7","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1158\/2159-8290.CD-19-0399","article-title":"Altered RNA processing in cancer pathogenesis and therapy","volume":"9","author":"Obeng","year":"2019","journal-title":"Cancer Discov"},{"key":"2026071706064931100_bib8","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s40364-020-00220-5","article-title":"The biological function and clinical significance of SF3B1 mutations in cancer","volume":"8","author":"Zhou","year":"2020","journal-title":"Biomark Res"},{"key":"2026071706064931100_bib9","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1038\/onc.2015.318","article-title":"Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes","volume":"35","author":"Sveen","year":"2016","journal-title":"Oncogene"},{"key":"2026071706064931100_bib10","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.celrep.2018.01.088","article-title":"Somatic mutational landscape of splicing factor genes and their functional consequences across 33 cancer types","volume":"23","author":"Seiler","year":"2018","journal-title":"Cell Rep"},{"key":"2026071706064931100_bib11","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1159\/000502888","article-title":"Mutations of GNAQ, GNA11, SF3B1, EIF1AX, PLCB4 and CYSLTR in uveal melanoma in Chinese patients","volume":"63","author":"Hou","year":"2020","journal-title":"Ophthalmic Res"},{"key":"2026071706064931100_bib12","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nature11547","article-title":"Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes","volume":"491","author":"Biankin","year":"2012","journal-title":"Nature"},{"key":"2026071706064931100_bib13","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1038\/s41588-019-0451-6","article-title":"Publisher correction: the long tail of oncogenic drivers in prostate cancer","volume":"51","author":"Armenia","year":"2019","journal-title":"Nat Genet"},{"key":"2026071706064931100_bib14","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.3390\/cancers11101439","article-title":"Splicing machinery is dysregulated in pituitary neuroendocrine tumors and is associated with aggressiveness features","volume":"11","author":"V\u00e1zquez-Borrego","year":"2019","journal-title":"Cancers"},{"key":"2026071706064931100_bib15","doi-asserted-by":"crossref","first-page":"4870","DOI":"10.1111\/j.1742-4658.2011.08387.x","article-title":"Biological validation that SF3b is a target of the antitumour macrolide pladienolide","volume":"278","author":"Yokoi","year":"2011","journal-title":"FEBS J"},{"key":"2026071706064931100_bib16","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1038\/nm.4165","article-title":"Therapeutic targeting of splicing in cancer","volume":"22","author":"Lee","year":"2016","journal-title":"Nat Med"},{"key":"2026071706064931100_bib17","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.molcel.2018.03.011","article-title":"Structural basis of splicing modulation by antitumour macrolide compounds","volume":"70","author":"Cretu","year":"2018","journal-title":"Mol Cel"},{"key":"2026071706064931100_bib18","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/cas.12317","article-title":"High antitumour activity of pladienolide B and its derivative in gastric cancer","volume":"105","author":"Sato","year":"2014","journal-title":"Cancer Sci"},{"key":"2026071706064931100_bib19","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.canlet.2020.10.010","article-title":"Splicing factor SF3B1 is overexpressed and implicated in the aggressiveness and survival of hepatocellular carcinoma","volume":"496","author":"L\u00f3pez-C\u00e1novas","year":"2021","journal-title":"Cancer Lett"},{"key":"2026071706064931100_bib20","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.trsl.2019.07.001","article-title":"Spliceosome component SF3B1 as novel prognostic biomarker and therapeutic target for prostate cancer","volume":"212","author":"Jim\u00e9nez-Vacas","year":"2019","journal-title":"Transl Res"},{"key":"2026071706064931100_bib21","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1186\/s13046-021-02153-9","article-title":"Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug","volume":"40","author":"Alors-Perez","year":"2021","journal-title":"J Exp Clin Cancer Res"},{"key":"2026071706064931100_bib22","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1080\/21691401.2019.1596922","article-title":"Inhibition of SF3b1 by pladienolide B evokes cycle arrest, apoptosis induction and p73 splicing in human cervical carcinoma cells","volume":"47","author":"Zhang","year":"2019","journal-title":"Artif Cells Nanomed Biotechnol"},{"key":"2026071706064931100_bib23","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13046-022-02241-4","article-title":"SF3B1 inhibition disrupts malignancy and prolongs survival in glioblastoma patients through BCL2L1 splicing and mTOR\/\u00df-catenin pathways imbalances","volume":"41","author":"Fuentes-Fayos","year":"2022","journal-title":"J Exp Clin Cancer Res"},{"key":"2026071706064931100_bib24","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s40478-025-02040-w","article-title":"Impaired splicing machinery in craniopharyngiomas unveils PRPF8 and RAVER1 as novel biomarkers and therapeutic targets","volume":"13","author":"Fuentes-Fayos","year":"2025","journal-title":"Acta Neuropathol Commun"},{"key":"2026071706064931100_bib25","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.canlet.2009.06.034","article-title":"The dopamine-somatostatin chimeric compound BIM-23A760 exerts antiproliferative and cytotoxic effects in human non-functioning pituitary tumors by activating ERK1\/2 and p38 pathways","volume":"288","author":"Peverelli","year":"2010","journal-title":"Cancer Lett"},{"key":"2026071706064931100_bib26","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1002\/ijc.30613","article-title":"Dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists are effective in inhibiting proliferation of progenitor\/stemlike cells isolated from nonfunctioning pituitary tumors","volume":"140","author":"Peverelli","year":"2017","journal-title":"Int J Cancer"},{"key":"2026071706064931100_bib27","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.1210\/en.2014-1063","article-title":"Filamin A (FLNA) plays an essential role in somatostatin receptor 2 (SST2) signaling and stabilization after agonist stimulation in human and rat somatotroph tumour cells","volume":"155","author":"Peverelli","year":"2014","journal-title":"Endocrinology"},{"key":"2026071706064931100_bib28","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1159\/000509219","article-title":"Beta-arrestin 2 is required for dopamine receptor type 2 inhibitory effects on AKT phosphorylation and cell proliferation in pituitary tumors","volume":"111","author":"Mangili","year":"2021","journal-title":"Neuroendocrinology"},{"key":"2026071706064931100_bib29","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.canlet.2016.08.005","article-title":"Dopamine receptor type 2 (DRD2) inhibits migration and invasion of human tumourous pituitary cells through ROCK-mediated cofilin inactivation","volume":"381","author":"Peverelli","year":"2016","journal-title":"Cancer Lett"},{"key":"2026071706064931100_bib30","doi-asserted-by":"crossref","first-page":"3104","DOI":"10.1158\/0008-5472.CAN-13-2235","article-title":"Identification and characterization of small molecules that inhibit nonsense-mediated RNA decay and suppress nonsense p53 mutations","volume":"74","author":"Martin","year":"2014","journal-title":"Cancer Res"},{"key":"2026071706064931100_bib31","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.molcel.2005.01.010","article-title":"SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway","volume":"17","author":"Fukuhara","year":"2005","journal-title":"Mol Cel"},{"key":"2026071706064931100_bib32","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1158\/2159-8290.CD-19-1330","article-title":"Mutations in the RNA splicing factor SF3B1 promote tumourigenesis through MYC stabilization","volume":"10","author":"Liu","year":"2020","journal-title":"Cancer Discov"},{"key":"2026071706064931100_bib33","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.celrep.2015.09.053","article-title":"Cancer-associated SF3B1 hotspot mutations induce cryptic 3\u2032 splice site selection through use of a different branch point","volume":"13","author":"Darman","year":"2015","journal-title":"Cell Rep"},{"key":"2026071706064931100_bib34","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/S1097-2765(03)00443-X","article-title":"Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7","volume":"12","author":"Ohnishi","year":"2003","journal-title":"Mol Cel"},{"key":"2026071706064931100_bib35","doi-asserted-by":"crossref","DOI":"10.1016\/j.bcp.2020.114039","article-title":"Targeting the spliceosome machinery: a new therapeutic axis in cancer?","volume":"189","author":"Eymin","year":"2021","journal-title":"Biochem Pharmacol"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/aop\/ERC-25-0527\/ERC-25-0527.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/aop\/ERC-25-0527\/ERC-25-0527.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-25-0527\/519696\/erc-25-0527.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-25-0527\/519696\/erc-25-0527.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T10:06:59Z","timestamp":1784282819000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/33\/7\/e250527\/77519\/Characterization-of-SF3B1-role-in-prolactin"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":35,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1530\/erc-25-0527","relation":{},"ISSN":["1351-0088","1479-6821"],"issn-type":[{"value":"1351-0088","type":"print"},{"value":"1479-6821","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]},"article-number":"e250527"}}