The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitises human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation
The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitises human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation
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DOI：
10.1016/j.ejca.2009.06.024
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发表时间：
2009-09-01
影响因子：
8.4
通讯作者：
Tesoriere, Giovanni
中科院分区：
文献类型：
--
作者：
Carlisi, Daniela;Lauricella, Marianna;Tesoriere, Giovanni
在亚毒性剂量下，组蛋白去乙酰酶抑制剂SAHA对TRAIL诱导人肝癌细胞(HepG2、Hep3B和SK-Hep1)的凋亡敏感，而对原代人肝细胞(PHHs)无效。尤其是在肝癌细胞中，SAHA使死亡受体5(DRS)的表达增加，c-Flip表达减少。这两个修饰是在TRAIL存在的情况下引起的，TRAIL-Disk的快速产生和caspase-8的激活。因此，SAHA/TRAIL结合诱导了许多细胞凋亡事件，如Bid裂解成TbID，线粒体膜电位消失，caspase-3激活，进而导致核因子-kappaB和Akt的裂解。核因子-kappaB水平的降低可能是IAP家族抗凋亡蛋白含量减少的原因，Akt水平的降低可能是导致磷酸化Bad减少的原因。这些事件导致caspase-9的激活，从而导致TRAIL的强大的凋亡活性。SAHA对TRAIL诱导的人肝癌细胞凋亡的敏感性可能为肝癌的治疗提供新的策略。(C)2009爱思唯尔有限公司。保留所有权利。
This paper shows that the histone deacetylase inhibitor SAHA sensitised at sub-toxic doses human hepatocellular carcinoma cells (HepG2, Hep3B and SK-Hep1) to TRAIL-induced apoptosis, while it was ineffective in primary human hepatocytes (PHHs).In particular in HCC cells SAHA increased the expression of death receptor 5 (DRS) and caused a decrement of c-Flip. These two modifications provoked in the presence of TRAIL the rapid production of TRAIL-DISC and the activation of caspase-8. Consequently SAHA/TRAIL combination induced many apoptotic events, such as a cleavage of Bid into tBid, dissipation of mitochondrial membrane potential, activation of caspase-3 with the consequent cleavage of both NF-kappa B and Akt. The decrease in NF-kappa B level seemed to be responsible for the reduction in the content of IAP family antiapoptotic proteins while the decrease in Akt level caused a reduction in phospho-Bad. These events led to the activation of caspase-9, which contributed to the strong apoptotic activity of TRAIL.Sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by SAHA may suggest new strategies for the treatment of liver tumours. (C) 2009 Elsevier Ltd. All rights reserved.