{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:43:46Z","timestamp":1788327826362,"version":"build-2803163510"},"reference-count":34,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T00:00:00Z","timestamp":1602892800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01-DE021139"],"award-info":[{"award-number":["R01-DE021139"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01-DE023220"],"award-info":[{"award-number":["R01-DE023220"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Dent Res"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:p>Patients with advanced salivary gland mucoepidermoid carcinoma (MEC) are treated with surgery and radiotherapy, as current systemic therapies are largely ineffective. As such, current treatment frequently leads to poor long-term survival due to locoregional recurrence or metastases. We have shown that salivary gland cancer stem cells (CSCs) are resistant to platinum-based chemotherapy and drive tumor progression. The purpose of this study was to investigate the effect of therapeutic inhibition of mTOR (mechanistic target of rapamycin) on resistance of CSCs to cisplatin, a prototypic platinum-based chemotherapeutic agent. Viability assays determined the effect of several inhibitors of PI3k\/mTOR signaling (e.g., temsirolimus, BKM120, AZD8055, PF4708671) and\/or cisplatin on survival of human MEC cells. The impact of mTOR inhibitors and\/or cisplatin on MEC stemness was examined with salisphere assays, flow cytometry for ALDH\/CD44 (CSC markers for MEC), and Western blots for Bmi-1 expression (marker of stem cell self-renewal). Salivary gland MEC patient-derived xenografts were used to examine the effect of cisplatin and\/or temsirolimus on CSCs in vivo. We observed that cisplatin induced mTOR and S6K1 phosphorylation, increased the number and size of MEC salispheres, and induced Bmi-1 expression and the fraction of CSCs in MEC models in vitro. Cisplatin also increased the fraction of CSCs in vivo. In contrast, mTOR inhibition (e.g., temsirolimus) blocked cisplatin-induced Bmi-1 expression and salisphere formation in vitro. Remarkably, temsirolimus slowed down tumor growth and decreased the fraction of CSCs ( P &lt; 0.05) even in presence of cisplatin in a short-term in vivo experiment. Collectively, these results demonstrate that therapeutic inhibition of mTOR ablates cytotoxic-resistant CSCs, and they suggest that a combination of an mTOR inhibitor and platinum-based chemotherapy might be beneficial to patients with salivary gland mucoepidermoid carcinoma.<\/jats:p>","DOI":"10.1177\/0022034520965141","type":"journal-article","created":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T05:46:10Z","timestamp":1602913570000},"page":"377-386","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":21,"title":["mTOR Inhibition Ablates Cisplatin-Resistant Salivary Gland Cancer Stem Cells"],"prefix":"10.1177","volume":"100","author":[{"given":"T.","family":"Nakano","sequence":"first","affiliation":[{"name":"Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA"},{"name":"Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.A.","family":"Warner","sequence":"additional","affiliation":[{"name":"Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.E.","family":"Oklejas","sequence":"additional","affiliation":[{"name":"Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Rodriguez-Ramirez","sequence":"additional","affiliation":[{"name":"Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.G.","family":"Shuman","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, School of Medicine, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4056-0235","authenticated-orcid":false,"given":"J.E.","family":"N\u00f6r","sequence":"additional","affiliation":[{"name":"Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA"},{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, School of Medicine, University of Michigan, Ann Arbor, MI, USA"},{"name":"Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, MI, USA"},{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2020,10,17]]},"reference":[{"key":"bibr1-0022034520965141","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5782"},{"key":"bibr2-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2013.05.013"},{"key":"bibr3-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2007.10.007"},{"key":"bibr4-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2016.12.016"},{"key":"bibr5-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0530291100"},{"key":"bibr6-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-2730"},{"key":"bibr7-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1038\/nature07733"},{"key":"bibr8-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-1630"},{"key":"bibr9-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2006.10.043"},{"key":"bibr10-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1038\/nature11287"},{"key":"bibr11-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1002\/hed.23600"},{"key":"bibr12-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbior.2014.05.001"},{"key":"bibr13-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.11.008"},{"key":"bibr14-0022034520965141","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.363"},{"key":"bibr15-0022034520965141","doi-asserted-by":"crossref","unstructured":"Janku F, Yap TA, Meric-Bernstam F. 2018. 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