{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T20:47:36Z","timestamp":1790369256782,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T00:00:00Z","timestamp":1585872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Differentiation therapy is an alternative strategy used to induce the differentiation of blast cells toward mature cells and to inhibit tumor cell proliferation for cancer treatment. Nobiletin (NOB), a polymethoxyflavone phytochemical, is present abundantly in citrus peels and has been reported to possess anti-cancer activity. In this study, we investigated the anti-leukemic effects of NOB on cell differentiation and its underlying mechanisms in human chronic myeloid leukemia (CML) K562 cells. NOB (100 \u03bcM) treatment for 24 and 48 h significantly decreased viability of K562 cells to 54.4 \u00b1 5.3% and 46.2 \u00b1 9.9%, respectively. NOB (10\u2013100 \u03bcM) significantly inhibited cell growth in K562 cells. Flow cytometry analysis and immunoblotting data showed that NOB (40 and 80 \u03bcM) could modulate the cell cycle regulators including p21, p27, and cyclin D2, and induce G1 phase arrest. NOB also increased the messenger RNA (mRNA) and protein expression of megakaryocytic differentiation markers, such as CD61, CD41, and CD42 as well as the formation of large cells with multi-lobulated nuclei in K562 cells. These results suggested that NOB facilitated K562 cells toward megakaryocytic differentiation. Furthermore, microarray analysis showed that expression of EGR1, a gene associated with promotion of megakaryocytic differentiation, was markedly elevated in NOB-treated K562 cells. The knockdown of EGR1 expression by small interference RNA (siRNA) could significantly attenuate NOB-mediated cell differentiation. We further elucidated that NOB induced EGR1 expression and CD61 expression through increases in MAPK\/ERK phosphorylation in K562 cells. These results indicate that NOB promotes megakaryocytic differentiation through the MAPK\/ERK pathway-dependent EGR1 expression in human CML cells. In addition, NOB when combined with imatinib could synergistically reduce the viability of K562 cells. Our findings suggest that NOB may serve as a beneficial anti-leukemic agent for differentiation therapy.<\/jats:p>","DOI":"10.3390\/cells9040877","type":"journal-article","created":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T03:58:39Z","timestamp":1586231919000},"page":"877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Nobiletin Promotes Megakaryocytic Differentiation through the MAPK\/ERK-Dependent EGR1 Expression and Exerts Anti-Leukemic Effects in Human Chronic Myeloid Leukemia (CML) K562 Cells"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2551-350X","authenticated-orcid":false,"given":"Jui-Hung","family":"Yen","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8543-5059","authenticated-orcid":false,"given":"Ching-Yen","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Hsien","family":"Chuang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1367-1757","authenticated-orcid":false,"given":"Hsien-Kuo","family":"Chin","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3327-828X","authenticated-orcid":false,"given":"Ming-Jiuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Yi","family":"Chen","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1126\/science.2406902","article-title":"Induction of chronic myelogenous leukemia in mice by the P210bcr\/abl gene of the Philadelphia chromosome","volume":"247","author":"Daley","year":"1990","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4808","DOI":"10.1182\/blood-2008-07-077958","article-title":"Translation of the Philadelphia chromosome into therapy for CML","volume":"112","author":"Druker","year":"2008","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/nm0596-561","article-title":"Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells","volume":"2","author":"Druker","year":"1996","journal-title":"Nat. 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