HDAC inhibitor PAC-320 induces G2/M cell cycle arrest and apoptosis in human prostate cancer.
HDAC inhibitor PAC-320 induces G2/M cell cycle arrest and apoptosis in human prostate cancer.
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HDAC 抑制剂 PAC-320 诱导人前列腺癌 G2/M 细胞周期停滞和细胞凋亡
DOI：
10.18632/oncotarget.23070
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发表时间：
2018-01-02
期刊：
影响因子：
--
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Dong Z;Yang Y;Liu S;Lu J;Huang B;Zhang Y
HDAC抑制剂（HDACis）已被证明在各种肿瘤类型中具有显著的抗增殖活性。先前，我们基于我们的p21荧光素酶启动子系统筛选了几种聚氧乙烯酸HDACis，并证明了这样的HDACis具有抗肿瘤活性。在此，我们进一步研究了聚氧乙烯酸盐中的一种化合物PAC-320在人前列腺癌中的抗肿瘤机制。我们证明PAC-320是一种广谱HDACi，在体外和体内都能抑制前列腺癌细胞的生长。此外，我们发现PAC-320诱导细胞周期停滞在G2/M期和凋亡。PAC-320诱导细胞周期阻滞的机制与p21蛋白表达增加、cyclin A和cyclin B1蛋白表达减少有关，而PAC-320诱导细胞凋亡的机制与线粒体凋亡途径有关，并与BH 3-only蛋白Noxa和Hrk表达增加密切相关。同时，我们证明p38 MAPK通路参与PAC-320诱导的前列腺癌抗增殖活性。综上所述，我们的数据表明，PAC-320在体外和体内具有有效的前列腺癌抑制活性，这是通过G2/M细胞周期阻滞和凋亡介导的。
HDAC inhibitors (HDACis) have been demonstrated with profound antiproliferative activities in various tumor types. Previously, we screened several polyoxometalate HDACis based on our p21 luciferase promoter system and demonstrated that such HDACis have antitumor activity. Here, we further investigate the antitumor mechanism of PAC-320, a compound among the polyoxometalates, in human prostate cancer. We demonstrate that PAC-320 is a broad-spectrum HDACi and could inhibit growth of prostate cancer cells in vitro and in vivo. Furthermore, we find that PAC-320 induces cell cycle arrest at G2/M phase and apoptosis. Mechanically, PAC-320 induced cell cycle arrest is associated with an increase of p21 and decrease of cyclin A and cyclin B1, while PAC-320 induced apoptosis is mediated through mitochondria apoptotic pathway and is closely associated with increase of BH3-only proteins Noxa and Hrk. Meanwhile, we demonstrate that p38 MAPK pathway is involved in PAC-320 induced antiproliferative activities in prostate cancer. Taken together, our data indicates that PAC-320 has potent prostate cancer inhibitory activity in vitro and in vivo, which is mediated by G2/M cell cycle arrest and apoptosis.
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