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首页> 外文期刊>Journal of cellular physiology. >NOXA-mediated degradation of MCL1 and BCL2L1 causes apoptosis of daunorubicin-treated human acute myeloid leukemia cells
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NOXA-mediated degradation of MCL1 and BCL2L1 causes apoptosis of daunorubicin-treated human acute myeloid leukemia cells

机译：NOXA-mediated MCL1和BCL2L1退化导致细胞凋亡daunorubicin-treated人类急性髓系白血病细胞

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Daunorubicin (DNR) is used clinically to treat acute myeloid leukemia (AML), while the signaling pathways associated with its cytotoxicity are not fully elucidated. Thus, we investigated the DNR-induced death pathway in the human AML cell lines U937 and HL-60. DNR-induced apoptosis in U937 cells accompanied by downregulation of MCL1 and BCL2L1, upregulation of Phorbol-12-myristate-13-acetate-induced protein 1 (NOXA), and mitochondrial depolarization. DNR induced NOX4-mediated reactive reactive oxygen species (ROS) production, which in turn inactivated Akt and simultaneously activated p38 mitogen-activated protein kinase (MAPK). Activated p38 MAPK and inactivated Akt coordinately increased GSK3β-mediated cAMP response element-binding protein (CREB) phosphorylation, which promoted NOXA transcription. NOXA upregulation critically increased the proteasomal degradation of MCL1 and BCL2L1. The same pathway was also responsible for the DNR-induced death of HL-60 cells. Restoration of MCL1 or BCL2L1 expression alleviated DNR-induced mitochondrial depolarization and cell death. Furthermore, ABT-199 (a BCL2 inhibitor) synergistically enhanced the cytotoxicity of DNR in AML cell lines. Notably, DNR-induced DNA damage was not related to NOXA-mediated degradation of MCL1 and BCL2L1. Collectively, these results indicate that the upregulation of NOXA expression through the NOX4-ROS-p38 MAPK-GSK3β-CREB axis results in the degradation of MCL1 and BCL2L1 in DNR-treated U937 and HL-60 cells. This signaling pathway may provide insights into the mechanism underlying DNR-triggered apoptosis in AML cells.
机译：道诺霉素临床医嘱)是用于治疗急性髓系白血病(AML),而信号通路与其细胞毒性不关联完全阐明。DNR-induced死亡通路在人类AML细胞U937和HL-60行。U937细胞MCL1的差别伴随着对这些BCL2L1, upregulationPhorbol-12-myristate-13-acetate-induced蛋白1(病因)和线粒体去极化。诱导NOX4-mediated被动的活性氧物种(ROS)生产,反过来灭活Akt p38同时激活增殖蛋白激酶(MAPK)。p38 MAPK和灭活Akt激活GSK3协调增加β介导的阵营反应元件结合蛋白(分子)磷酸化,从而促进了病因转录。增加了MCL1的蛋白酶体降解BCL2L1。DNR-induced HL-60的死亡细胞。MCL1或缓解BCL2L1表达式DNR-induced线粒体去极化和细胞死亡。协同增强医嘱的细胞毒性在AML细胞株。损坏是NOXA-mediated无关退化MCL1和BCL2L1。这些结果表明,upregulation通过NOX4-ROS-p38病因表达式MAPK-GSK3β分子轴导致退化MCL1和BCL2L1 DNR-treated U937和HL-60细胞。洞察潜在的机制DNR-triggered在AML细胞凋亡。

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