The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitises human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation

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• 作者：Daniela Carlisi ; Marianna Lauricella ; Antonella D’ ; Anneo ; Sonia Emanuele ; Liliana Angileri ; Pietro Di Fazio ; Andrea Santulli ; Renza Vento ; Giovanni Tesoriere
• 关键词：TRAIL ; SAHA ; HCC cells ; DR5 ; NF-kB ; Akt
• 刊名：European Journal of Cancer
• 出版年：2009
• 出版时间：September 2009
• 年：2009
• 卷：45
• 期：13
• 页码：2425-2438
• 全文大小：931 K

文摘

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.