{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:55:45Z","timestamp":1788306945181,"version":"build-2803163510"},"reference-count":0,"publisher":"Bioscientifica","issue":"8","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,8,1]]},"abstract":"\n Cushing\u2019s disease (CD) is a rare endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor. Pasireotide is the only pituitary-targeted drug approved for adult patients. Nevertheless, many side effects are encountered and curative therapy is still challenging. Ubiquitin-specific peptidase 8 (USP8) plays a crucial role in the modulation of corticotroph cells growth and ACTH secretion. Here, we explored the anticancer potential of the USP8 inhibitor RA-9 in USP8-WT human tumor corticotroph cells and murine AtT-20 cells. Our results showed that RA-9 causes cell proliferation decrease (\u221224.3 \u00b1 5.2%,\n P<\/jats:italic>\n < 0.01) and cell apoptosis increase (207.4 \u00b1 75.3%,\n P<\/jats:italic>\n < 0.05) in AtT-20 cells, as observed with pasireotide. Moreover, RA-9 reduced ACTH secretion in AtT-20 cells (\u221234.1 \u00b1 19.5%,\n P<\/jats:italic>\n < 0.01), as well as in AtT-20 cells transfected with USP8 mutants, and in one out of two primary cultures\n in vitro<\/jats:italic>\n responsive to pasireotide (\u221240.3 \u00b1 6%). An RA-9 mediated decrease of pERK1\/2 levels was observed in AtT-20 cells (\u221252.3 \u00b1 13.4%,\n P<\/jats:italic>\n < 0.001), comparable to pasireotide, and in primary cultures, regardless of their\n in vitro<\/jats:italic>\n responsiveness to pasireotide. Upregulation of p27 was detected upon RA-9 treatment only, both in AtT-20 cells (167.1 \u00b1 36.7%,\n P<\/jats:italic>\n < 0.05) and in one primary culture tested (168.4%), whilst pCREB level was similarly halved in AtT-20 cells by both RA-9 and pasireotide. Altogether, our data demonstrate that RA-9 is efficient in exerting cytotoxic effects and inhibitory actions on cell proliferation and hormone secretion by modulating the expression of pERK1\/2, pCREB and p27. Inhibition of USP8 might represent a novel strategy to target both USP8-WT and USP8-mutated tumors in CD patients.\n <\/jats:p>","DOI":"10.1530\/erc-21-0093","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T12:45:35Z","timestamp":1622810735000},"page":"573-582","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":23,"title":["USP8 inhibitor RA-9 reduces ACTH release and cell growth in tumor corticotrophs"],"prefix":"10.1530","volume":"28","author":[{"given":"Donatella","family":"Treppiedi","sequence":"first","affiliation":[{"name":"1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genesio","family":"Di Muro","sequence":"additional","affiliation":[{"name":"1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giusy","family":"Marra","sequence":"additional","affiliation":[{"name":"1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Barbieri","sequence":"additional","affiliation":[{"name":"1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Mangili","sequence":"additional","affiliation":[{"name":"1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Catalano","sequence":"additional","affiliation":[{"name":"1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"Serban","sequence":"additional","affiliation":[{"name":"2Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Ferrante","sequence":"additional","affiliation":[{"name":"2Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Locatelli","sequence":"additional","affiliation":[{"name":"3Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy"},{"name":"4Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Neurosurgery Unit, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea G","family":"Lania","sequence":"additional","affiliation":[{"name":"5Humanitas Clinical and Research Center IRCCS, Endocrinology, Diabetology and Medical Andrology Unit, Milan, Italy"},{"name":"6Department of Biomedical Sciences, Humanitas University, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Arosio","sequence":"additional","affiliation":[{"name":"1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"},{"name":"2Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Spada","sequence":"additional","affiliation":[{"name":"1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Peverelli","sequence":"additional","affiliation":[{"name":"1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Mantovani","sequence":"additional","affiliation":[{"name":"1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy"},{"name":"2Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","container-title":["Endocrine-Related Cancer"],"original-title":[],"link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/28\/8\/ERC-21-0093.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/28\/8\/ERC-21-0093.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:56:00Z","timestamp":1784555760000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/erc\/article\/28\/8\/573-582\/25679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,1]]},"references-count":0,"journal-issue":{"issue":"8"},"URL":"https:\/\/doi.org\/10.1530\/erc-21-0093","relation":{},"ISSN":["1351-0088","1479-6821"],"issn-type":[{"value":"1351-0088","type":"print"},{"value":"1479-6821","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,1]]}}}