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While GPER targeting has been widely studied in the context of solid tumors, its effect on hematological malignancies remains to be fully understood. Here, we show that GPER1 mRNA is down-regulated in plasma cells from overt multiple myeloma (MM) and plasma cell leukemia patients as compared to normal donors or pre-malignant conditions (monoclonal gammopathy of undetermined significance and smoldering MM); moreover, lower GPER1 expression associates with worse overall survival of MM patients. Using the clinically applicable GPER1-selective agonist G-1, we demonstrate that the pharmacological activation of GPER1 triggered in vitro anti-MM activity through apoptosis induction, also overcoming the protective effects exerted by bone marrow stromal cells. Noteworthy, G-1 treatment reduced in vivo MM growth in two distinct xenograft models, even bearing bortezomib-resistant MM cells. Mechanistically, G-1 upregulated the miR-29b oncosuppressive network, blunting an established miR-29b-Sp1 feedback loop operative in MM cells. Overall, this study highlights the druggability of GPER1 in MM, providing the first preclinical framework for further development of GPER1 agonists to treat this malignancy.<\/jats:p>","DOI":"10.3390\/cells12182226","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T09:56:36Z","timestamp":1694080596000},"page":"2226","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["GPER1 Activation Exerts Anti-Tumor Activity in Multiple Myeloma"],"prefix":"10.3390","volume":"12","author":[{"given":"Maria Eugenia","family":"Gallo Cantafio","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Torcasio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"},{"name":"Laboratory of Cellular and Molecular Cardiovascular Pathophysiology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8149-7957","authenticated-orcid":false,"given":"Francesca","family":"Scionti","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Science, University Magna Graecia, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5455-168X","authenticated-orcid":false,"given":"Maria","family":"Mesuraca","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4824-3445","authenticated-orcid":false,"given":"Domenica","family":"Ronchetti","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20141 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1219-0038","authenticated-orcid":false,"given":"Mariaelena","family":"Pistoni","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9986-456X","authenticated-orcid":false,"given":"Dina","family":"Bellizzi","sequence":"additional","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4701-9748","authenticated-orcid":false,"given":"Giuseppe","family":"Passarino","sequence":"additional","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugenio","family":"Morelli","sequence":"additional","affiliation":[{"name":"Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonino","family":"Neri","sequence":"additional","affiliation":[{"name":"Scientific Directorate, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Viglietto","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Amodio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hideshima, T., and Anderson, K.C. 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