title: Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Shanghai, China.
authors.forename: Zhen-Bin
authors.initials: ZB
authors.lastname: Ding
authors.forename: Bo
authors.initials: B
authors.lastname: Hui
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Shi
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Yuan-Fei
authors.initials: YF
authors.lastname: Peng
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Gu
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Guo-Ming
authors.initials: GM
authors.lastname: Shi
authors.forename: Ai-Wu
authors.initials: AW
authors.lastname: Ke
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Wang
authors.forename: Kang
authors.initials: K
authors.lastname: Song
authors.forename: Zhi
authors.initials: Z
authors.lastname: Dai
authors.forename: Ying-Hao
authors.initials: YH
authors.lastname: Shen
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin; D002738:Chloroquine