Arsenic sulfide promotes apoptosis in retinoid acid resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein.
Arsenic sulfide promotes apoptosis in retinoid acid resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein.
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DOI：
10.1371/journal.pone.0083184
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Tian Y;Liu Y;He P;Liu F;Zhou N;Cheng X;Shi L;Zhu H;Zhao J;Wang Y;Zhang M
四砷四硫醚（As4S4）是一种具有抗肿瘤活性的砷化合物，特别是对维甲酸（RA）有抗性的急性早幼粒细胞白血病（APL）。虽然最近的研究表明As4S4的治疗作用与诱导细胞凋亡密切相关，但As4S4在ra耐药APL中的确切分子机制尚不清楚。本研究发现，在抗ra的NB4-R1细胞中，as4s4诱导的凋亡伴随着SET基因mRNA和蛋白表达的降低。此外，RNAi敲低SET基因进一步促进了As4S4诱导的细胞凋亡，而SET过表达则抑制了As4S4诱导的细胞凋亡，提示As4S4通过降低NB4-R1细胞中SET蛋白诱导细胞凋亡。我们还发现，SET基因的敲低导致早幼粒细胞白血病蛋白磷酸酶2 （PP2A）表达上调，维甲酸受体α融合基因（PML-RARα）表达下调，As4S4处理增强了这一表达。相比之下，SET基因的过表达导致PP2A下调和PML-RARα上调，而As4S4预处理可以消除这些上调。由于PP2A是促凋亡因子，PMLRARα是抗凋亡因子，我们的研究结果表明，as4s4诱导NB4-R1细胞凋亡是通过下调SET蛋白表达，从而升高PP2A，降低PML-RARα表达，导致细胞凋亡。
Tetra-arsenic tetra-sulfide (As4S4) is an arsenic compound with anti-tumor activity, especially in acute promyelocytic leukemia (APL) that are resistant to retinoic acid (RA). Although recent studies revealed that the therapeutic action of As4S4 is closely associated with the induction of cellular apoptosis, the exact molecular mechanism of action of As4S4 in RA-resistant APL remains to be clarified. In this study, we found that As4S4-induced apoptosis was accompanied by reduced mRNA and protein expression of SET gene in RA-resistant NB4-R1 cells. Moreover, RNAi knockdown of SET gene further promoted As4S4-induced apoptosis, while SET over-expression inhibited it, suggesting that As4S4 induces apoptosis through the reduction of SET protein in NB4-R1 cells. We also demonstrated that the knockdown of SET gene resulted in the upregulation of protein phosphatase 2 (PP2A) expression and the downregulation of promyelocytic leukemia and retinoic acid receptor α fusion gene (PML-RARα) expression, which were enhanced by As4S4 treatments. By contrast, over-expression of SET gene resulted in PP2A downregulation and PML-RARα upregulation, which were abolished by As4S4 pretreatment. Since PP2A is a pro-apoptotic factor and PMLRARα is an anti-apoptotic factor, our results suggest that As4S4-induced apoptosis in NB4-R1 cells is through the downregulation of SET protein expression, which in turn increases PP2A and reduces PML-RARα expressions to lead to cell apoptosis.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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发表时间：
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影响因子：
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作者：
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