{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:44:25Z","timestamp":1791999865315,"version":"4.4.0"},"reference-count":30,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T00:00:00Z","timestamp":1646006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000646","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K11058"],"award-info":[{"award-number":["18K11058"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>6-O-Carboxypropyl-alpha-tocotrienol (\u03b1-T3E) is a multi-target redox-silent analogue of tocotrienol that exhibits cytotoxicity against many cancer cells, including malignant mesothelioma (MM) cells. \u03b1-T3E has several molecular targets to effectively induce cytotoxicity against MM cells; however, the mechanisms underlying this cytotoxicity remain unclear. In the present study, we demonstrated that the \u03b1-T3E-dependent disruption of the homeostasis of proteasomes strongly induced endoplasmic reticulum (ER) stress, which resulted in effective cytotoxicity against MM cells. The \u03b1-T3E-dependent disruption of the homeostasis of proteasomes depended on decreases in proteasome subunits via the inactivation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor erythroid 2 related factor-1 (NRF1), which inhibited protease activity, such as chymotrypsin-like activity, in proteasomes. The \u03b1-T3E-dependent inhibition of this activity also induced severe ER stress and ultimately resulted in effective cytotoxicity against MM cells with chemoresistance. The present results indicate that \u03b1-T3E acts as an effective anti-mesothelioma agent by disrupting the homeostasis of proteasomes through the simultaneous inactivation of STAT3 and NRF1.<\/jats:p>","DOI":"10.3390\/ijms23052655","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T20:11:14Z","timestamp":1646079074000},"page":"2655","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Redox-Silent Analogue of Tocotrienol May Break the Homeostasis of Proteasomes in Human Malignant Mesothelioma Cells by Inhibiting STAT3 and NRF1"],"prefix":"10.3390","volume":"23","author":[{"given":"Kyota","family":"Ishii","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Bromacology, Graduate School of Food and Nutritional Sciences, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Momoka","family":"Fusegi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Bromacology, Graduate School of Food and Nutritional Sciences, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuki","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Food and Life Sciences, Faculty of Food and Nutritional Sciences, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Teshima","sequence":"additional","affiliation":[{"name":"Department of Food and Life Sciences, Faculty of Food and Nutritional Sciences, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanako","family":"Ninomiya","sequence":"additional","affiliation":[{"name":"Department of Food and Life Sciences, Faculty of Food and Nutritional Sciences, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kakeru","family":"Kohno","sequence":"additional","affiliation":[{"name":"Research Institute of Life Innovation, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayami","family":"Sato","sequence":"additional","affiliation":[{"name":"Research Institute of Life Innovation, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Ishida","sequence":"additional","affiliation":[{"name":"Research Institute of Life Innovation, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Miyakoshi","sequence":"additional","affiliation":[{"name":"Research Institute of Life Innovation, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9490-3424","authenticated-orcid":false,"given":"Tomohiro","family":"Yano","sequence":"additional","affiliation":[{"name":"Research Institute of Life Innovation, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1053\/j.semtcvs.2014.08.003","article-title":"Novel induction therapies for pleural mesothelioma","volume":"26","author":"Donahoe","year":"2014","journal-title":"Semin. 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