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Toxins 2015, 7(8), 3030-3044; doi:10.3390/toxins7083030

Citreoviridin Induces Autophagy-Dependent Apoptosis through Lysosomal-Mitochondrial Axis in Human Liver HepG2 Cells

1
Department of Preventive Medicine, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China
2
Liaoning Anti-Degenerative Diseases Natural Products Engineering Research Center, Dalian Medical University, 9 W Lvshun South Road, Dalian 116044, China
*
Authors to whom correspondence should be addressed.
Academic Editor: Paul Turner
Received: 5 July 2015 / Revised: 27 July 2015 / Accepted: 31 July 2015 / Published: 6 August 2015
(This article belongs to the Section Mycotoxins)
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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. View Full-Text
Keywords: citreoviridin; autophagy; apoptosis; lysosomal membrane permeabilization; human liver HepG2 cells citreoviridin; autophagy; apoptosis; lysosomal membrane permeabilization; human liver HepG2 cells
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Wang, Y.; Liu, Y.; Liu, X.; Jiang, L.; Yang, G.; Sun, X.; Geng, C.; Li, Q.; Yao, X.; Chen, M. Citreoviridin Induces Autophagy-Dependent Apoptosis through Lysosomal-Mitochondrial Axis in Human Liver HepG2 Cells. Toxins 2015, 7, 3030-3044.

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