Simultaneous inhibition of DNA methyltransferase and histone deacetylase induces p53-independent apoptosis via down-regulation of Mcl-1 in acute myelogenous leukemia cells
Simultaneous inhibition of DNA methyltransferase and histone deacetylase induces p53-independent apoptosis via down-regulation of Mcl-1 in acute myelogenous leukemia cells
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DOI：
10.1016/j.leukres.2011.04.004
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发表时间：
2011-07-01
影响因子：
2.7
通讯作者：
Yokoyama, Akihito
中科院分区：
文献类型：
--
作者：
Nishioka, Chie;Ikezoe, Takayuki;Yokoyama, Akihito
我们最近建立了MV 4 -11急性髓性白血病（AML）亚系，命名为MV 4 -11 TP 53 R248 W，其在TP 53基因中具有错义突变（CGG -> TGG; R248 W），导致该转录因子失活。DNA甲基转移酶（DNMT）抑制剂5-氮杂-2 '-脱氧胞苷（5-AzadC）诱导MV 4 -11细胞凋亡，但不诱导MV 4 -11 TP 53 R248 W细胞凋亡。另一类抗表观遗传剂组蛋白脱乙酰酶抑制剂（HDACI）抑制MV 4 -11和MV 4 -11 TP 53 R248 W细胞的增殖。值得注意的是，当5-AzadC与HDACI MS-275组合时，MV 4 -11 TP 53 R248 W细胞中的细胞凋亡显著增强，与半胱天冬酶级联的激活、p21（waf 1）和γ-H2 AX的上调以及Mcl-1的下调平行。有趣的是，通过泛半胱天冬酶抑制剂抑制半胱天冬酶3减弱了MV 4 -11 TP 53 R248 W细胞中5-AzadC和MS-275介导的细胞凋亡和Mcl-1下调的组合。此外，在MV 4 -11 R248 W细胞中，小干扰RNA下调p21（waf 1）的表达可抑制5-AzadC和MS-275联合作用后caspase 3的激活，表明p21（waf 1）在激活caspase 3中的作用。总之，在AML细胞中，不依赖于TP 53的p21（waf 1）上调激活caspase 3，下调Mcl-1。5-AzadC和MS-275的组合可能是TP 53失活的白血病个体的有希望的治疗策略。(C)2011爱思唯尔有限公司保留所有权利。
We have recently established the MV4-11 acute myelogenous leukemia (AML) subline, designated as MV4-11 TP53 R248W, which possesses a missense mutation (CGG -> TGG; R248W) in the TP53 gene, leading to inactivation of this transcription factor. DNA methyltransferase (DNMT) inhibitor 5-Aza-2'-deoxycytidine (5-AzadC) induced apoptosis in MV4-11, but not in MV4-11 TP53 R248W cells. Another class of anti-epigenetic agent histone deacetylase inhibitor (HDACI) inhibited the proliferation of both MV4-11 and MV4-11 TP53 R248W cells. Notably, when 5-AzadC was combined with HDACI MS-275, apoptosis in MV4-11 TP53 R248W cells was significantly enhanced in parallel with activation of the caspase cascade, up-regulation of p21(waf1) and gamma-H2AX, and down-regulation of Mcl-1. Interestingly, inhibition of caspase 3 by the pan-caspase inhibitor attenuated the combination of 5-AzadC and MS-275-mediated apoptosis and down-regulation of Mcl-1 in MV4-11 TP53 R248W cells. Moreover, down-regulation of p21(waf1) in MV4-11 R248W cells by a small interfering RNA blunted activation of caspase 3 after exposure to the combination of 5-AzadC and MS-275, indicating the role of p21(waf1) to activate caspase 3.Taken together, TP53-independent up-regulation of p21(waf1) activates caspase 3 and down-regulates Mcl-1 in AML cells. Combination of 5-AzadC and MS-275 may be a promising treatment strategy for individuals with leukemia in which TP53 is inactivated. (C) 2011 Elsevier Ltd. All rights reserved.