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Thus, we investigated the DNR\u2010induced death pathway in the human AML cell lines U937 and HL\u201060. DNR\u2010induced apoptosis in U937 cells accompanied by downregulation of MCL1 and BCL2L1, upregulation of Phorbol\u201012\u2010myristate\u201013\u2010acetate\u2010induced protein 1 (NOXA), and mitochondrial depolarization. DNR induced NOX4\u2010mediated reactive reactive oxygen species (ROS) production, which in turn inactivated Akt and simultaneously activated p38 mitogen\u2010activated protein kinase (MAPK). Activated p38 MAPK and inactivated Akt coordinately increased GSK3\u03b2\u2010mediated cAMP response element\u2010binding protein (CREB) phosphorylation, which promoted <jats:italic>NOXA<\/jats:italic> transcription. NOXA upregulation critically increased the proteasomal degradation of MCL1 and BCL2L1. The same pathway was also responsible for the DNR\u2010induced death of HL\u201060 cells. Restoration of MCL1 or BCL2L1 expression alleviated DNR\u2010induced mitochondrial depolarization and cell death. Furthermore, ABT\u2010199 (a BCL2 inhibitor) synergistically enhanced the cytotoxicity of DNR in AML cell lines. Notably, DNR\u2010induced DNA damage was not related to NOXA\u2010mediated degradation of MCL1 and BCL2L1. Collectively, these results indicate that the upregulation of NOXA expression through the NOX4\u2010ROS\u2010p38 MAPK\u2010GSK3\u03b2\u2010CREB axis results in the degradation of MCL1 and BCL2L1 in DNR\u2010treated U937 and HL\u201060 cells. This signaling pathway may provide insights into the mechanism underlying DNR\u2010triggered apoptosis in AML cells.<\/jats:p>","DOI":"10.1002\/jcp.30407","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T10:01:45Z","timestamp":1620900105000},"page":"7356-7375","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["NOXA\u2010mediated degradation of MCL1 and BCL2L1 causes apoptosis of daunorubicin\u2010treated human acute myeloid leukemia cells"],"prefix":"10.1002","volume":"236","author":[{"given":"Jing\u2010Ting","family":"Chiou","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences National Sun Yat\u2010Sen University Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan\u2010Chieh","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Family Medicine Zuoying Branched of Kaohsiung Armed Forces General 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