{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T20:58:11Z","timestamp":1790542691296,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,1,16]],"date-time":"2019-01-16T00:00:00Z","timestamp":1547596800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["26460624"],"award-info":[{"award-number":["26460624"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2019,2]]},"abstract":"Inactivation of the TP<\/jats:styled-content>53<\/jats:italic> tumor suppressor gene is essential during cancer development and progression. Mutations of TP<\/jats:styled-content>53<\/jats:italic> are often missense and occur in various human cancers. In some fraction of wild\u2010type (wt) TP<\/jats:styled-content>53<\/jats:italic> tumors, p53 is inactivated by upregulated murine double minute homolog 2 (MDM<\/jats:styled-content>2) and MDM<\/jats:styled-content>4. We previously reported that simultaneous knockdown of MDM<\/jats:styled-content>4<\/jats:italic> and MDM<\/jats:styled-content>2<\/jats:italic> using synthetic DNA<\/jats:styled-content>\u2010modified siRNA<\/jats:styled-content>s revived p53 activity and synergistically inhibited in vitro cell growth in cancer cells with wt TP<\/jats:styled-content>53<\/jats:italic> and high MDM<\/jats:styled-content>4 expression (wtTP<\/jats:styled-content>53<\/jats:italic>\/highMDM<\/jats:styled-content>4). In the present study, MDM<\/jats:styled-content>4<\/jats:italic>\/MDM<\/jats:styled-content>2<\/jats:italic> double knockdown with the siRNA<\/jats:styled-content>s enhanced 5\u2010fluorouracil (5\u2010FU<\/jats:styled-content>)\u2010induced p53 activation, arrested the cell cycle at G1<\/jats:sub> phase, and potentiated the antitumor effect of 5\u2010FU<\/jats:styled-content> in wtTP<\/jats:styled-content>53<\/jats:italic>\/highMDM<\/jats:styled-content>4\u00a0human colon (HCT<\/jats:styled-content>116 and LoVo) and gastric (SNU<\/jats:styled-content>\u20101 and NUGC<\/jats:styled-content>\u20104) cancer cells. Exposure to 5\u2010FU<\/jats:styled-content> alone induced MDM<\/jats:styled-content>2 as well as p21 and PUMA<\/jats:styled-content> by p53 activation. As p53\u2010MDM<\/jats:styled-content>2 forms a negative feedback loop, enhancement of the antitumor effect of 5\u2010FU<\/jats:styled-content> by MDM<\/jats:styled-content>4<\/jats:italic>\/MDM<\/jats:styled-content>2<\/jats:italic> double knockdown could be attributed to blocking of the feedback mechanism in addition to direct suppression of these p53 antagonists. Intratumor injection of the MDM<\/jats:styled-content>4\/MDM<\/jats:styled-content>2<\/jats:italic> siRNA<\/jats:styled-content>s suppressed in vivo tumor growth and boosted the antitumor effect of 5\u2010FU<\/jats:styled-content> in an athymic mouse xenograft model using HCT<\/jats:styled-content>116 cells. These results suggest that a combination of MDM<\/jats:styled-content>4<\/jats:italic>\/MDM<\/jats:styled-content>2<\/jats:italic> knockdown and conventional cytotoxic drugs could be a promising treatment strategy for wtTP<\/jats:styled-content>53<\/jats:italic>\/highMDM<\/jats:styled-content>4 gastrointestinal cancers.<\/jats:p>","DOI":"10.1111\/cas.13893","type":"journal-article","created":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T09:21:18Z","timestamp":1543483278000},"page":"639-649","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Augmented antitumor activity of 5\u2010fluorouracil by double knockdown of MDM<\/scp>4<\/i> and MDM<\/scp>2<\/i> in colon and gastric cancer cells"],"prefix":"10.1111","volume":"110","author":[{"given":"Mamiko","family":"Imanishi","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology Institute of Clinical Medicine Graduate School of Comprehensive Human Sciences University of Tsukuba Tsukuba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Institute of Clinical Medicine Graduate School of Comprehensive Human Sciences University of Tsukuba Tsukuba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Institute of Clinical Medicine Graduate School of Comprehensive Human Sciences University of Tsukuba Tsukuba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinori","family":"Sugaya","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Kasumigaura Medical Center Tsuchiura Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuaki","family":"Hirose","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Tsuchiura Clinical Education and Training Center University of Tsukuba Hospital Tsuchiura Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Endo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Institute of Clinical Medicine Graduate School of Comprehensive Human Sciences University of Tsukuba Tsukuba Japan"},{"name":"Department of Gastroenterology and Hepatology Shinmatsudo Central General Hospital Matsudo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukikazu","family":"Natori","sequence":"additional","affiliation":[{"name":"RNAi Company Ltd. 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