title: The oxidation states of DJ-1 dictate the cell fate in response to oxidative stress triggered by 4-hpr: autophagy or apoptosis?
abstract: OBJECTIVE
  Chemotherapy-induced reactive oxygen species (ROS) not only contribute to apoptosis, but also trigger autophagy. Since autophagy is reported to protect cancer cells from apoptosis, this weakens the therapeutic effect of chemotherapy. This study aimed at identifying the key molecules that determine the cellular response to ROS and, therefore, provide better strategies to increase chemotherapeutic efficiency.
  
  
  RESULTS
  Increasing concentrations of N-(4-hydroxyphenyl) retinamide (4-HPR)-treatment pushed autophagy down to apoptosis in a dose-dependent manner, and 4-HPR-induced ROS contribute to this process. Since we found that ASK1-regulated JNK1 and p38 are responsible for 4-HPR-induced autophagy and apoptosis, respectively, we further utilized co-immunoprecipitation followed by liquid chromatography-tandem mass spectrometry analysis to identify proteins that specifically bind to ASK1 under different oxidative states. Of note, DJ-1, a crucial antioxidant protein, was identified. Interestingly, DJ-1 functions as a redox sensor that senses ROS levels and determines the cellular response to 4-HPR: Under mild oxidative stress, moderate oxidation of DJ-1 is recruited to inhibit the activity of ASK1 and maintain cell viability by activating autophagy; under a lethal level of oxidative stress, excessive oxidized DJ-1 dissociates from ASK1 and activates it, thereby initiating p38 activation and enabling the cells to commit to apoptosis. Moreover, the depletion of DJ-1 increases the sensitivity of tumor cells to 4-HPR both in vitro and in vivo.
  
  
  METHODS
  Our results reveal that the different oxidation states of DJ-1 function as a cellular redox sensor of ROS caused by 4-HPR and determine the cell fate of autophagy or apoptosis. Moreover, the results suggest that DJ-1 might be a potent therapeutic target for cancer treatment.
  
  
  CONCLUSIONS
  ROS-mediated changes in the oxidation state of DJ-1 are involved in 4-HPR's effect on pushing autophagy down to apoptosis. Consequently, this change mediates ASK1 activation by regulating DJ-1-ASK1 complex formation and determines the cell fate of autophagy or apoptosis.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China .
authors.forename: Ji
authors.initials: J
authors.lastname: Cao
authors.forename: Meidan
authors.initials: M
authors.lastname: Ying
authors.forename: Nan
authors.initials: N
authors.lastname: Xie
authors.forename: Guanyu
authors.initials: G
authors.lastname: Lin
authors.forename: Rong
authors.initials: R
authors.lastname: Dong
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Hailin
authors.initials: H
authors.lastname: Yan
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Yang
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D019070:Cell Lineage; D017313:Fenretinide / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D015513:Oncogene Proteins / Q000737:chemistry*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D000071617:Protein Deglycase DJ-1; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; D017313:Fenretinide; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1