尽管阿糖胞苷（Ara-C）是急性髓系白血病（AML）的主要治疗方法，但其诱导细胞凋亡的细胞毒作用机制仍不清楚。因此，我们研究了Ara-C在人类AML U937细胞中诱导细胞死亡的通路。Ara-C诱导的MCL1下调与线粒体去极化和凋亡的诱导有关。Ara-C触发NOX4介导的ROS产生，进而激活p38 MAPK但使AKT失活。Ara-C诱导的DNA损伤调节p38 MAPK激活，但不影响U937细胞中AKT的失活。失活的AKT促进GSK3β依赖的CREB磷酸化，从而增加NOXA转录，进而触发MCL1蛋白的降解。活化的p38 MAPK引起HuR下调，导致加速MCL1 mRNA的降解。类似的通路也解释了Ara-C诱导的THP-1细胞死亡。综上所述，我们的数据证实了Ara-C在AML细胞系U937和THP-1中诱导细胞凋亡是通过不稳定MCL1 mRNA和蛋白进行介导的。此外，Ara-C与BCL2抑制剂ABT-199协同作用，通过抑制MCL1表达，在ABT-199耐药和亲本U937细胞中诱导细胞死亡。版权所有 © 2023 Elsevier Inc.。保留所有权利。

Although cytarabine (Ara-C) is the mainstay of treatment for acute myeloid leukemia (AML), its cytotoxic mechanisms for inducing apoptosis are poorly understood. Therefore, we investigated the Ara-C-induced cell death pathway in human AML U937 cells. Ara-C-induced downregulation of MCL1 is associated with the induction of mitochondrial depolarization and apoptosis. Ara-C triggered NOX4-mediated ROS production, which in turn activated p38 MAPK but inactivated AKT. Ara-C-induced DNA damage modulates p38 MAPK activation without affecting AKT inactivation in U937 cells. Inactivated AKT promotes GSK3β-dependent CREB phosphorylation, which in turn increases NOXA transcription, thereby triggering the degradation of MCL1 protein. Activated p38 MAPK induces HuR downregulation, leading to accelerated MCL1 mRNA turnover. A similar pathway also explains the Ara-C-induced THP-1 cell death. Collectively, our data confirm that Ara-C-triggered apoptosis in the AML cell lines U937 and THP-1 is mediated through the destabilization of MCL1 mRNA and protein. Furthermore, Ara-C acts synergistically with the BCL2 inhibitor ABT-199 to induce cell death in ABT-199-resistant and parental U937 cells by inhibiting MCL1 expression.Copyright © 2023 Elsevier Inc. All rights reserved.