Carlisi Daniela, Lauricella Marianna, D'Anneo Antonella, Emanuele Sonia, Angileri Liliana, Di Fazio Pietro, Santulli Andrea, Vento Renza, Tesoriere Giovanni
Dipartimento di Scienze Biochimiche, Università di Palermo, Policlinico, Palermo 90127, Italy.
Eur J Cancer. 2009 Sep;45(13):2425-38. doi: 10.1016/j.ejca.2009.06.024. Epub 2009 Jul 28.
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 (DR5) 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-kB and Akt. The decrease in NF-kB 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.
本文表明，组蛋白去乙酰化酶抑制剂SAHA在亚毒性剂量下可使人类肝癌细胞（HepG2、Hep3B和SK-Hep1）对TRAIL诱导的凋亡敏感，而在原代人肝细胞（PHHs）中则无效。特别是在肝癌细胞中，SAHA增加了死亡受体5（DR5）的表达，并导致c-Flip减少。在TRAIL存在的情况下，这两种修饰引发了TRAIL-DISC的快速产生和半胱天冬酶-8的激活。因此，SAHA/TRAIL组合诱导了许多凋亡事件，如Bid裂解为tBid、线粒体膜电位消散、半胱天冬酶-3激活以及随后NF-κB和Akt的裂解。NF-κB水平的降低似乎是IAP家族抗凋亡蛋白含量减少的原因，而Akt水平的降低导致磷酸化Bad减少。这些事件导致了半胱天冬酶-9的激活，这有助于TRAIL的强大凋亡活性。SAHA使人类肝癌细胞对TRAIL诱导的凋亡敏感，这可能为肝癌治疗提出新的策略。
