The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide (Retracted article. See vol. 95, pg. 336, 2019)
The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide (Retracted article. See vol. 95, pg. 336, 2019)
复制标题
DOI：
10.1124/mol.105.017145
复制
发表时间：
2006-01-01
影响因子：
3.6
通讯作者：
Grant, S
中科院分区：
文献类型：
--
作者：
Rosato, RR;Maggio, SC;Grant, S
在人白血病细胞（U937和Jurkat）中检测了新型组蛋白去乙酰化酶抑制剂（HDACI）LAQ 824诱导分化和凋亡的决定因素。将U937细胞暴露于低浓度的LAQ 824（30 nM）导致活性氧（ROS）延迟（2 h）增加、p21（WAF 1/CIP 1）诱导、pRb去磷酸化、细胞生长停滞在G（0）/G（1）期和分化。另一方面，将细胞暴露于较高浓度的LAQ 824（75 nM）导致ROS的早期（30 min）产生、细胞停滞在G（2）/M期、XIAP（在转录水平）和Mcl-1（通过半胱天冬酶介导的过程）的下调、神经酰胺的酸性鞘磷脂酶依赖性产生以及严重的线粒体损伤、半胱天冬酶激活和凋亡。LAQ 824诱导的U937细胞致死性不涉及外源性凋亡途径，也不与死亡受体上调相关;相反，它被Bcl-2、Bcl-x（L）、XIAP和Mcl-1的异位表达显著抑制。自由基清除剂N-乙酰半胱氨酸阻断LAQ 824介导的ROS产生、线粒体损伤、Mcl-1下调、神经酰胺产生和细胞凋亡，表明氧化损伤在LAQ 824致死性中的主要作用。总之，这些发现表明，LAQ 824诱导的致死率代表了一个多因素的过程，其中LAQ 824介导的ROS产生是必要的，但不足以诱导细胞凋亡，XIAP和Mcl-1下调和神经酰胺产生的程度决定了该试剂是否参与成熟而不是凋亡程序。
Determinants of differentiation and apoptosis induction by the novel histone deacetylase inhibitor (HDACI) LAQ824 were examined in human leukemia cells (U937 and Jurkat). Exposure of U937 cells to a low concentration of LAQ824 (30 nM) resulted in a delayed (2 h) increase in reactive oxygen species (ROS), induction of p21(WAF1/CIP1), pRb dephosphorylation, growth arrest of cells in G(0)/G(1) phase, and differentiation. On the other hand, exposure of cells to a higher concentration of LAQ824 (75 nM) resulted in the early (30 min) generation of ROS, arrest of cells in G(2)/M phase, down-regulation of XIAP (at the transcriptional level) and Mcl-1 (through a caspase-mediated process), the acid sphingomyelinase-dependent generation of ceramide, and profound mitochondrial injury, caspase activation, and apoptosis. LAQ824-induced lethality in U937 cells did not involve the extrinsic apoptotic pathway, nor was it associated with death receptor up-regulation; instead, it was markedly inhibited by ectopic expression of Bcl-2, Bcl-x(L), XIAP, and Mcl-1. The free radical scavenger N-acetyl cysteine blocked LAQ824-mediated ROS generation, mitochondrial injury, Mcl-1 down-regulation, ceramide generation, and apoptosis, suggesting a primary role for oxidative injury in LAQ824 lethality. Together, these findings indicate that LAQ824-induced lethality represents a multifactorial process in which LAQ824-mediated ROS generation is necessary but not sufficient to induce apoptosis, and that the degree of XIAP and Mcl-1 down-regulation and ceramide generation determines whether this agent engages a maturation rather than an apoptotic program.