Downregulation of topoisomerase IIβ in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation/growth arrest
Downregulation of topoisomerase IIβ in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation/growth arrest
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DOI：
10.1038/sj.leu.2404351
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发表时间：
2006-10-01
期刊：
影响因子：
11.4
通讯作者：
Ganapathi, R.
中科院分区：
文献类型：
--
作者：
Chikamori, K.;Hill, J. E.;Ganapathi, R.
在拓扑异构酶(Topo)II同工酶(α和β)中，Topo IIβ被认为是调节分化的酶。在这项研究中，我们研究了Topo IIβ在全反式维甲酸(ATRA)诱导髓系白血病细胞系分化中的作用。抑制Topo IIβ活性或下调蛋白表达可增强ATRA诱导的分化/生长停滞和细胞凋亡。全反式维甲酸诱导的Topo IIβ缺陷细胞的凋亡涉及caspase级联的激活，并被topo IIβ的异位表达所拯救。基因表达谱结果表明，在Topo IIβ缺陷细胞中，过氧化还蛋白2(PRDX2)是下调表达的候选基因。在Topo IIβ缺陷细胞中，PRDX2在mRNA和蛋白水平的表达减少与ATRA诱导分化后活性氧自由基(ROS)的积累有关。在Topo IIβ缺陷细胞中过表达PRDX2可减少ROS的积聚，并部分逆转ATRA诱导的细胞凋亡。这些结果支持Topo IIβ在全反式维甲酸分化的髓系白血病细胞存活中的作用。Topo IIβ的表达减少，部分是通过下调PRDX2而削弱细胞的抗氧化能力，从而诱导细胞凋亡。因此，抑制髓系白血病细胞中Topo IIβ和/或PRDX2的水平为改进基于ATRA的分化治疗提供了一种新的途径。
Among the topoisomerase ( topo) II isozymes ( alpha and beta), topo II beta has been suggested to regulate differentiation. In this study, we examined the role of topo II beta in all-trans retinoic acid ( ATRA)-induced differentiation of myeloid leukemia cell lines. Inhibition of topo II beta activity or downregulation of protein expression enhanced ATRA-induced differentiation/growth arrest and apoptosis. ATRA-induced apoptosis in topo II beta-deficient cells involved activation of the caspase cascade and was rescued by ectopic expression of topo II beta. Gene expression profiling led to the identification of peroxiredoxin 2 ( PRDX2) as a candidate gene that was downregulated in topo II beta-deficient cells. Reduced expression of PRDX2 validated at the mRNA and protein level, in topo II beta-deficient cells correlated with increased accumulation of reactive oxygen species ( ROS) following ATRA-induced differentiation. Overexpression of PRDX2 in topo II beta-deficient cells led to reduced accumulation of ROS and partially reversed ATRA-induced apoptosis. These results support a role for topo II beta in survival of ATRA-differentiated myeloid leukemia cells. Reduced expression of topo II beta induces apoptosis in part by impairing the anti-oxidant capacity of the cell owing to downregulation of PRDX2. Thus, suppression of topo II beta and/or PRDX2 levels in myeloid leukemia cells provides a novel approach for improving ATRA-based differentiation therapy.