Autophagy Activation in Hepatocellular Carcinoma Contributes to the Tolerance of Oxaliplatin via Reactive Oxygen Species Modulation
Autophagy Activation in Hepatocellular Carcinoma Contributes to the Tolerance of Oxaliplatin via Reactive Oxygen Species Modulation
复制标题
肝细胞癌中的自噬激活通过活性氧调节促进奥沙利铂的耐受性
DOI：
10.1158/1078-0432.ccr-11-0816
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发表时间：
2011-10-01
影响因子：
11.5
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Ding, Zhen-Bin;Hui, Bo;Fan, Jia
目的：了解哺乳动物自噬在癌症中的作用突出了自噬途径作为癌症治疗策略的药理学操作的最新进展。然而，自噬状态和相应的功能在肝细胞癌（HCC）治疗应激后仍有待澄清。本研究是为了确定是否可以激活化疗后的自噬机制和自噬的贡献，奥沙利铂在hcch.Experimental Design耐受性：自噬激活和奥沙利铂诱导的细胞死亡进行了检查，在两个肝癌细胞系，以及在体内使用肝癌模型在裸鼠。肝癌组织标本与或没有局部化疗手术前也检查了免疫组化和电子显微镜analysis.Results：自噬功能激活后，奥沙利铂治疗的肝癌细胞系和异种移植物。在HCC细胞中，使用药理学抑制剂或RNA干扰必需的自噬基因抑制自噬增强奥沙利铂诱导的细胞死亡。活性氧的产生在奥沙利铂联合自噬抑制剂诱导细胞死亡中具有重要作用。重要的是，奥沙利铂与自噬抑制剂氯喹的组合导致HCC异种移植物中更明显的肿瘤抑制。此外，自噬特异性蛋白LC 3和自噬自噬体形成诱导到一个显着较高的水平，在肝癌标本已进行局部chemotherapy.Conclusions：自噬激活治疗应激下有助于肝癌肿瘤细胞的生存。靶向自噬通路是一种有前途的治疗策略，可以增强化疗的效果，改善HCC患者的临床结局。临床癌症研究; 17（19）; 6229-38。(C)2011年AACR。
Purpose: Understanding the roles of mammalian autophagy in cancer highlights recent advances in the pharmacologic manipulation of autophagic pathways as a therapeutic strategy for cancer. However, autophagy status and corresponding functions in hepatocellular carcinoma (HCC) after therapeutic stress remain to be clarified. This study was to determine whether the autophagic machinery could be activated after chemotherapy and the contribution of autophagy to tolerance of oxaliplatin in HCC.Experimental Design: Autophagy activation and cell death induced by oxaliplatin were examined in two HCC cell lines as well as in vivo using an HCC model in nude mice. HCC tissue samples with or without locoregional chemotherapy before surgery were also examined by immunohistochemical and electron microscopic analysis.Results: Autophagy was functionally activated in HCC cell lines and xenografts after oxaliplatin treatment. Suppression of autophagy using either pharmacologic inhibitors or RNA interference of essential autophagy gene enhanced cell death induced by oxaliplatin in HCC cells. Generation of reactive oxygen species has an important role in the induction of cell death by oxaliplatin in combination with autophagy inhibitors. Critically, the combination of oxaliplatin with autophagy inhibitor chloroquine resulted in a more pronounced tumor suppression in HCC xenografts. Furthermore, autophagy-specific protein LC3 and autophagic autophagosome formation were induced to a significantly higher level in HCC specimens that had been subjected to locoregional chemotherapy.Conclusions: Autophagy activation under therapy stress contributes to HCC tumor cell survival. Targeting the autophagy pathway is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in HCC patients. Clin Cancer Res; 17(19); 6229-38. (C) 2011 AACR.