title: Protective effect of mild endoplasmic reticulum stress on radiation-induced bystander effects in hepatocyte cells.
abstract: Radiation-induced bystander effect (RIBE) has important implications for secondary cancer risk assessment during cancer radiotherapy, but the defense and self-protective mechanisms of bystander normal cells are still largely unclear. The present study found that micronuclei (MN) formation could be induced in the non-irradiated HL-7702 hepatocyte cells after being treated with the conditioned medium from irradiated hepatoma HepG2 cells under either normoxia or hypoxia, where the ratio of the yield of bystander MN induction to the yield of radiation-induced MN formation under hypoxia was much higher than that of normoxia. Nonetheless, thapsigargin induced endoplasmic reticulum (ER) stress and dramatically suppressed this bystander response manifested as the decrease of MN and apoptosis inductions. Meanwhile, the interference of BiP gene, a major ER chaperone, amplified the detrimental RIBE. More precisely, thapsigargin provoked ER sensor of PERK to initiate an instantaneous and moderate ER stress thus defensed the hazard form RIBE, while BiP depletion lead to persistently destroyed homeostasis of ER and exacerbated cell injury. These findings provide new insights that the mild ER stress through BiP-PERK-p-eIF2α signaling pathway has a profound role in protecting cellular damage from RIBE and hence may decrease the potential secondary cancer risk after cancer radiotherapy.
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China.|Central Laboratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ye
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Mingyuan
authors.initials: M
authors.lastname: He
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Tu
authors.affiliation: Central Laboratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Peifeng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Shao
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D017209:Apoptosis / Q000528:radiation effects; D024201:Bystander Effect / Q000528:radiation effects*; D015687:Cell Hypoxia; D017077:Culture Media, Conditioned; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000502:physiology / Q000528:radiation effects*; D006801:Humans; D015398:Signal Transduction; D019284:Thapsigargin / Q000008:administration & dosage; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D017077:Culture Media, Conditioned; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D019284:Thapsigargin; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase