{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T00:38:56Z","timestamp":1760834336880,"version":"build-2065373602"},"reference-count":24,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Carfilzomib, a second\u2010generation proteasome inhibitor approved for the treatment of multiple myeloma, is a highly potent and selective inhibitor of the CT\u2010L activity of the i20S proteasome. Several studies have shown that carfilzomib (CFZ) can bypass resistance to bortezomib; however, its impact on squamous cell carcinoma of the head and neck is not well understood. This study aimed to evaluate the anticancer potential of CFZ in head and neck cancer cells (HNSCC) by examining its effects on proliferation, apoptosis, and the underlying mechanisms in both HPV\u2010positive and HPV\u2010negative HNSCC. In Vitro validation of CFZ showed an IC50 that was more than fourfold lower in HPV\u2010negative CAL\u201027 than other HNSCC cell lines. In addition, CFZ inhibited p\u2010Akt and p\u2010S6 and activated p21, which increased growth inhibition and apoptosis in CAL\u201027 cells. In mice bearing xenografted HPV\u2010negative CAL\u201027 cells, we confirmed that CFZ reduced tumor growth. Collectively, the cytotoxic effects induced by CFZ involve cell growth inhibition and apoptosis via the PI3K\/AKT\/mTOR and p21 signaling pathways. This suggests that CFZ is a novel therapeutic agent that can overcome the existing cisplatin resistance used in the treatment of HPV\u2010negative HNSCC.<\/jats:p>","DOI":"10.1002\/mc.70029","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T06:36:43Z","timestamp":1755671803000},"page":"1838-1850","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Noncanonical Pathways of Proteasome Inhibition in HPV\u2010Negative Head &amp; Neck Cancer"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2643-3929","authenticated-orcid":false,"given":"Hye\u2010Yeon","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology\u2013Head &amp; Neck Surgery, Seoul National University Bundang Hospital Seoul National University College of Medicine Seongnam Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7020-1320","authenticated-orcid":false,"given":"Ji\u2010Yeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2013Head &amp; Neck Surgery, Seoul National University Bundang Hospital Seoul National University College of Medicine Seongnam Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2761-9871","authenticated-orcid":false,"given":"Zhiyong","family":"Wang","sequence":"additional","affiliation":[{"name":"Stomatology Hospital, School of Stomatology Zhejiang University School of Medicine Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8089-1488","authenticated-orcid":false,"given":"Panomwat","family":"Amornphimoltham","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, Faculty of Dentistry Mahidol University Bangkok Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5150-4482","authenticated-orcid":false,"given":"J. 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