Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe.
Histone deacetylase inhibitors promote glioma cell death by G2 checkpoint abrogation leading to mitotic catastrophe.
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DOI：
10.1038/cddis.2014.412
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发表时间：
2014-10-02
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
多形性胶质母细胞瘤由于其浸润性质和复发能力而对常规抗肿瘤治疗具有抗性;因此，研究工作集中于表征胶质瘤形成和鉴定对治疗有用的分子靶标。正在患者中测试新的治疗策略，例如组蛋白脱乙酰酶抑制剂（HDACi）单独或与其他疗法组合。在这里，已经测试了临床试验中包括的两种HDACi，辛二酰异羟肟酸（SAHA）和丙戊酸（VPA），以表征它们对体外胶质瘤细胞生长的影响，并确定促进癌细胞死亡的分子变化。我们发现HDACi降低胶质瘤细胞活力、增殖和克隆形成。它们具有多种作用，例如诱导活性氧（ROS）的产生和激活线粒体凋亡途径，然而，泛半胱天冬酶抑制剂Q-VD-OPh不能阻止细胞死亡。重要的是，我们发现HDACi通过降低G2检查点激酶Wee 1和检查点激酶1（Chk 1）的表达来改变细胞周期进程。此外，HDACi降低神经胶质瘤细胞和人多形性胶质母细胞瘤原代培养物中参与DNA修复（Rad 51）、有丝分裂纺锤体形成（TPX 2）和染色体分离（Survivin）的蛋白质的表达。因此，HDACi治疗导致神经胶质瘤细胞在DNA损伤可以被修复之前进入有丝分裂，并导致异常有丝分裂纺锤体的形成，其通过有丝分裂灾难诱导的细胞凋亡导致神经胶质瘤细胞死亡。
Glioblastoma multiforme is resistant to conventional anti-tumoral treatments due to its infiltrative nature and capability of relapse; therefore, research efforts focus on characterizing gliomagenesis and identifying molecular targets useful on therapy. New therapeutic strategies are being tested in patients, such as Histone deacetylase inhibitors (HDACi) either alone or in combination with other therapies. Here two HDACi included in clinical trials have been tested, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), to characterize their effects on glioma cell growth in vitro and to determine the molecular changes that promote cancer cell death. We found that both HDACi reduce glioma cell viability, proliferation and clonogenicity. They have multiple effects, such as inducing the production of reactive oxygen species (ROS) and activating the mitochondrial apoptotic pathway, nevertheless cell death is not prevented by the pan-caspase inhibitor Q-VD-OPh. Importantly, we found that HDACi alter cell cycle progression by decreasing the expression of G2 checkpoint kinases Wee1 and checkpoint kinase 1 (Chk1). In addition, HDACi reduce the expression of proteins involved in DNA repair (Rad51), mitotic spindle formation (TPX2) and chromosome segregation (Survivin) in glioma cells and in human glioblastoma multiforme primary cultures. Therefore, HDACi treatment causes glioma cell entry into mitosis before DNA damage could be repaired and to the formation of an aberrant mitotic spindle that results in glioma cell death through mitotic catastrophe-induced apoptosis.
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星形胶质瘤和正常脑组织中的12个组蛋白脱乙酰基酶（HDAC）基因的差异表达：II和IV类在胶质母细胞瘤中不表达。
影响因子：
3.8
作者：
Lucio-Eterovic AK;Cortez MA;Valera ET;Motta FJ;Queiroz RG;Machado HR;Carlotti CG Jr;Neder L;Scrideli CA;Tone LG
通讯作者：
Tone LG
DOI：
10.1073/pnas.0409130102
发表时间：
2005-01-25
影响因子：
11.1
作者：
Huang, XX;Tran, T;Zhang, PM
通讯作者：
Zhang, PM
DOI：
10.1158/1078-0432.ccr-12-0647
发表时间：
2013-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Guvenc H;Pavlyukov MS;Joshi K;Kurt H;Banasavadi-Siddegowda YK;Mao P;Hong C;Yamada R;Kwon CH;Bhasin D;Chettiar S;Kitange G;Park IH;Sarkaria JN;Li C;Shakhparonov MI;Nakano I
通讯作者：
Nakano I
影响因子：
7.5
作者：
Lens, Susanne M. A.;Vader, Gerben;Medema, Rene H.
通讯作者：
Medema, Rene H.
影响因子：
8
作者：
Castedo, M;Perfettini, JL;Kroemer, G
通讯作者：
Kroemer, G