title: Citreoviridin Induces Autophagy-Dependent Apoptosis through Lysosomal-Mitochondrial Axis in Human Liver HepG2 Cells.
abstract: Citreoviridin (CIT) is a mycotoxin derived from fungal species in moldy cereals. In our previous study, we reported that CIT stimulated autophagosome formation in human liver HepG2 cells. Here, we aimed to explore the relationship of autophagy with lysosomal membrane permeabilization and apoptosis in CIT-treated cells. Our data showed that CIT increased the expression of LC3-II, an autophagosome biomarker, from the early stage of treatment (6 h). After treatment with CIT for 12 h, lysosomal membrane permeabilization occurred, followed by the release of cathepsin D in HepG2 cells. Inhibition of autophagosome formation with siRNA against Atg5 attenuated CIT-induced lysosomal membrane permeabilization. In addition, CIT induced collapse of mitochondrial transmembrane potential as assessed by JC-1 staining. Furthermore, caspase-3 activity assay showed that CIT induced apoptosis in HepG2 cells. Inhibition of autophagosome formation attenuated CIT-induced apoptosis, indicating that CIT-induced apoptosis was autophagy-dependent. Cathepsin D inhibitor, pepstatin A, relieved CIT-induced apoptosis as well, suggesting the involvement of the lysosomal-mitochondrial axis in CIT-induced apoptosis. Taken together, our data demonstrated that CIT induced autophagy-dependent apoptosis through the lysosomal-mitochondrial axis in HepG2 cells. The study thus provides essential mechanistic insight, and suggests clues for the effective management and treatment of CIT-related diseases.
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. wangyuexia1990@hotmail.com.|Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. wangyuexia1990@hotmail.com.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. liuyanan_sh@hotmail.com.|Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. liuyanan_sh@hotmail.com.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. food@dlmedu.edu.cn.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. jianglipingdl@163.com.|Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. jianglipingdl@163.com.
authors.forename: Liping
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. yg290@163.com.
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, China. sunxiance@gmail.com.|Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. sunxiance@gmail.com.
authors.forename: Xiance
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. gengchengyandl@gmail.com.
authors.forename: Chengyan
authors.initials: C
authors.lastname: Geng
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. liqiujuandl@gmail.com.
authors.forename: Qiujuan
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. yaoxiaofeng79@hotmail.com.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China. chenmin_dl@hotmail.com.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001313:Aurovertins / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009183:Mycotoxins / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects
chemical_list: D001313:Aurovertins; D009183:Mycotoxins; D053148:Caspase 3; C014416:citreoviridin
keywords: apoptosis; autophagy; citreoviridin; human liver HepG2 cells; lysosomal membrane permeabilization