title: Citreoviridin induces ROS-dependent autophagic cell death in human liver HepG2 cells.
abstract: Citreoviridin (CIT) is one of toxic mycotoxins derived from fungal species in moldy cereals. Whether CIT exerts hepatotoxicity and the precise molecular mechanisms of CIT hepatotoxicity are not completely elucidated. In this study, the inhibitor of autophagosome formation, 3-methyladenine, protected the cells against CIT cytotoxicity, and the autophagy stimulator rapamycin further decreased the cell viability of CIT-treated HepG2 cells. Knockdown of Atg5 with Atg5 siRNA alleviated CIT-induced cell death. These finding suggested the hypothesis that autophagic cell death contributed to CIT-induced cytotoxicity in HepG2 cells. CIT increased the autophagosome number in HepG2 cells observed under a transmission electron microscope, and this effect was confirmed by the elevated LC3-II levels detected through Western blot. Reduction of P62 protein levels and the result of LC3 turnover assay indicated that the accumulation of autophagosomes in the CIT-treated HepG2 cells was due to increased formation rather than impaired degradation. The pretreatment of HepG2 cells with the ROS inhibitor NAC reduced autophagosome formation and reversed the CIT cytotoxicity, indicating that CIT-induced autophagic cell death was ROS-dependent. In summary, ROS-dependent autophagic cell death of HpeG2 cells described in this study may help to elucidate the underlying mechanism of CIT cytotoxicity.
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian, 116044, PR China; Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, 9 W Lvshun South Road, Dalian, 116044, PR China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Liu
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian, 116044, PR China; Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, 9 W Lvshun South Road, Dalian, 116044, PR China.
authors.forename: Yue-Xia
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian, 116044, PR China.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Liu
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian, 116044, PR China; Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, 9 W Lvshun South Road, Dalian, 116044, PR China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Jiang
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian, 116044, PR China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian, 116044, PR China; Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, 9 W Lvshun South Road, Dalian, 116044, PR China.
authors.forename: Xian-Ce
authors.initials: XC
authors.lastname: Sun
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian, 116044, PR China.
authors.forename: Cheng-Yan
authors.initials: CY
authors.lastname: Geng
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian, 116044, PR China.
authors.forename: Qiu-Juan
authors.initials: QJ
authors.lastname: Li
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian, 116044, PR China. Electronic address: chenmin_sh@163.com.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian, 116044, PR China. Electronic address: yaoxiaofeng79@163.com.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001313:Aurovertins / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000235:genetics; D010588:Phagosomes / Q000187:drug effects; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C502778:ATG5 protein, human; D001313:Aurovertins; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; C025946:3-methyladenine; D000225:Adenine; C014416:citreoviridin
keywords: Autophagy; Citreoviridin; Human liver HepG2 cells; Reactive oxygen species