{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T11:11:18Z","timestamp":1783941078695,"version":"3.55.0"},"reference-count":79,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T00:00:00Z","timestamp":1699488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Else Kr\u00f6ner-Fresenius Foundation","award":["1"],"award-info":[{"award-number":["1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Drug resistance is a common cause of therapy failure in head and neck squamous cell carcinoma (HNSCC). One approach to tackling it is by targeting fundamental cellular processes, such as translation. The eukaryotic translation initiation factor 2\u03b1 (EIF2\u03b1) is a key player in canonical translation initiation and integrates diverse stress signals; when phosphorylated, it curbs global protein synthesis. This study evaluates EIF2\u03b1 expression and phosphorylation in HNSCC. A small-molecule inhibitor of EIF2\u03b1 dephosphorylation, salubrinal, was tested in vitro, followed by viability assays, flow cytometry, and immunoblot analyses. Patient-derived 3D tumor spheres (PD3DS) were cultured with salubrinal and their viability assessed. Lastly, salubrinal was evaluated with standard-of-care chemotherapeutics. Our analysis of RNA and proteomics data shows elevated EIF2\u03b1 expression in HNSCC. Immunohistochemical staining reveals increasing EIF2\u03b1 abundance from premalignant lesions to invasive and metastatic carcinoma. In immunoblots from intraoperative samples, EIF2\u03b1 expression and steady-state phosphorylation are higher in HNSCC than in neighboring normal tissue. Inhibition of EIF2\u03b1 dephosphorylation decreases HNSCC cell viability and clonogenic survival and impairs the G1\/S transition. Salubrinal also decreases the viability of PD3DS and acts synergistically with cisplatin, 5-fluorouracil, bleomycin, and proteasome inhibitors. Our results indicate that pharmacological inhibition of EIF2\u03b1 dephosphorylation is a potential therapeutic strategy for HNSCC.<\/jats:p>","DOI":"10.3390\/cancers15225350","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T10:19:27Z","timestamp":1699525167000},"page":"5350","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Inhibition of EIF2\u03b1 Dephosphorylation Decreases Cell Viability and Synergizes with Standard-of-Care Chemotherapeutics in Head and Neck Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Anna M.","family":"Cyran","sequence":"first","affiliation":[{"name":"Legorreta Cancer Center, Department of Pathology and Laboratory Medicine, Brown University, Providence, RI 02906, USA"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Otto-von-Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Kleinegger","sequence":"additional","affiliation":[{"name":"Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2563-0386","authenticated-orcid":false,"given":"Norbert","family":"Nass","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Brandenburg, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8060-2313","authenticated-orcid":false,"given":"Michael","family":"Naumann","sequence":"additional","affiliation":[{"name":"Institute of Experimental Internal Medicine, Otto von Guericke University, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Haybaeck","sequence":"additional","affiliation":[{"name":"Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8072-1438","authenticated-orcid":false,"given":"Christoph","family":"Arens","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Giessen and Marburg University Hospitals, Campus Giessen, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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