{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:37:28Z","timestamp":1786113448085,"version":"build-2736575974"},"reference-count":34,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:p>\n                    Irinotecan, a topoisomerase I (topoI) inhibitor, is widely used for colorectal cancer, but resistance remains a major clinical challenge. We previously showed that camptothecin induces ubiquitin\u2013proteasome pathway (UPP)\u2010mediated topoI degradation. In this study, we investigated whether inhibition of UPP could prevent topoI degradation and restore camptothecin sensitivity. SN\u201038, an active metabolite of irinotecan, induced topoI degradation in irinotecan\u2010resistant colorectal cancer cell lines, which was suppressed by ixazomib. The combination significantly enhanced cytotoxicity, colony inhibition, and reduced IC\n                    <jats:sub>50<\/jats:sub>\n                    values compared with SN\u201038 alone. Mechanistically, ixazomib prevented proteasome\u2010mediated degradation of ubiquitinated topoI, restoring its stability.\n                    <jats:italic>In vivo,<\/jats:italic>\n                    the combination significantly suppressed tumor growth in a DLD\u20101 xenograft model compared with SN\u201038 alone. These findings indicate that UPP\u2010dependent topoI degradation is a key mechanism underlying irinotecan resistance in colorectal cancer. Pharmacological inhibition of the proteasome effectively prevents topoI loss and restores irinotecan sensitivity, suggesting that proteasome inhibitors such as ixazomib may serve as promising therapeutic partners for camptothecin\u2010based chemotherapy.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70256","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T06:41:12Z","timestamp":1776321672000},"page":"2114-2128","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteasome inhibitor, ixazomib prevents topoisomerase\u2010I degradation and reverses irinotecan resistance in colorectal cancer"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5636-3236","authenticated-orcid":false,"given":"Yuho","family":"Ebata","sequence":"first","affiliation":[{"name":"Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0149-1505","authenticated-orcid":false,"given":"Koji","family":"Ando","sequence":"additional","affiliation":[{"name":"Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Hasuda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery and Clinical Research Institute Kyushu Medical Center  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koshi","family":"Mimori","sequence":"additional","affiliation":[{"name":"Department of Surgery Kyushu University Beppu Hospital  Oita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Unan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology Oncology Boston University School of Medicine  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddhartha","family":"Pulukuri","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology Oncology Boston University School of Medicine  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aahana","family":"Tiku","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology Oncology Boston University School of Medicine  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Berger","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceutical Company Limited  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Oki","sequence":"additional","affiliation":[{"name":"Department of Advanced Medicine and Innovative Technology Kyushu University Hospital  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajit","family":"Bharti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology Oncology Boston University School of Medicine  Boston MA USA"},{"name":"Predictus Bioscience Inc.  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