Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma
Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma
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DOI：
10.4161/auto.6.8.13365
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发表时间：
2010-11-16
期刊：
影响因子：
13.3
通讯作者：
Chen, Ching-Chow
中科院分区：
文献类型：
--
作者：
Liu, Yuan-Ling;Yang, Pei-Ming;Chen, Ching-Chow
肝细胞癌（HCC）是世界上第五大常见癌症和第三大癌症死亡原因。HCC的药物治疗在很大程度上是不成功的。组蛋白去乙酰化酶抑制剂可以重新激活肿瘤细胞中的肿瘤抑制基因，成为潜在的抗癌药物。透射电镜、免疫荧光和LC3-II积累显示，两种有效的HDAC抑制剂OSU-HDAC42和SAHA诱导HCC细胞自噬。我们发现SAHA和OSU-HDAC42通过下调Akt/mTOR信号和诱导内质网应激反应诱导自噬。通过敲除3-MA或Atg5抑制自噬可降低saha诱导的细胞毒性，表明saha诱导的自噬可导致细胞死亡。我们的研究结果表明，自噬诱导剂与SAHA联合治疗HCC可能具有吸引力，自噬的药理靶向为癌症治疗的管理提供了希望。
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Drug treatments for HCC have been largely unsuccessful. Histone deacetylase inhibitors can reactivate tumor suppressor genes in cancer cells and serve as potential anti-cancer drugs. Two potent HDAC inhibitors OSU-HDAC42 and SAHA induced autophagy in HCC cells as revealed by transmission electron microscopy, immunofluorescence and LC3-II accumulation. We found that SAHA and OSU-HDAC42 induced autophagy through downregulation of Akt/mTOR signaling and induction of ER stress response. Inhibition of autophagy by 3-MA or Atg5 knockout reduced SAHA-induced cytotoxicity, indicating that SAHA-induced autophagy led to cell death. Our results show that the combination of autophagy inducers with SAHA might be attractive for the treatment of HCC and pharmacological targeting of autophagy provides promise for the management of cancer therapy.