Journal
TOXICOLOGY LETTERS
Volume 301, Issue -, Pages 1-10Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2018.10.026
Keywords
HERP; Autophagy; Zearalenone; Apoptosis; Granulosa cells
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Funding
- National Natural Science Foundation of China [31702298, 31772817, 31771301, 31602125]
- Natural Science Foundation of Jiangsu Province, China [BK20170498]
- China Postdoctoral Science Foundation [2017M621843, 2017M61065, 2018T111112]
- Natural Science Foundation of Jiangsu Higher Education Institutions of China [17KJD230002]
- Priority Academic Program Development of Jiangsu Higher Education Institution (PAPD)
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HERP is an endoplasmic reticulum (ER) membrane protein and is strongly induced by stress conditions. A recent study has indicated that HERP cooperates in apoptosis during zearalenone (ZEA) treatment. However, regulatory mechanisms and the role of HERP in ZEA-induced apoptosis remain elusive in ovarian granulosa cells. In this study, MTT and flow cytometry assays demonstrated that ZEA gradually decreased cell viability and increased apoptosis in granulosa cells in a dose-dependent manner. Western blot analysis showed that ZEA significantly activated autophagy by upregulating LC3-II. Chloroquine (CQ) significantly increased LC3-II and induced granulosa cell apoptosis. Moreover, Western blot analysis showed that ZEA inhibited the mTOR and ERK1/2 signaling pathways. Furthermore, we found that ZEA activated ER stress by upregulating the ER stress-related proteins GRP78, HERP and CHOP. 4-PBA significantly decreased GRP78, HERP, CHOP and LC3-II. In addition, knockdown of HERP (shHERP) significantly protected ovarian granulosa cells from apoptosis induced by ZEA. We found that HERP depletion activated autophagy and ERK1/2 signaling pathways, while it inhibited the mTOR and caspase-dependent mitochondrial signaling pathways. In summary, autophagy and ER stress cooperated in apoptosis induced by ZEA; HERP depletion inhibits ZEA-induced apoptosis of ovarian granulosa cells through autophagy activation and apoptotic pathway inhibition.
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