NF-κB/mTOR-mediated autophagy can regulate diquat-induced apoptosisNF-kappa B/mTOR-mediated autophagy can regulate diquat-induced apoptosis
- Other Titles
- NF-kappa B/mTOR-mediated autophagy can regulate diquat-induced apoptosis
- Authors
- Park, Aeri; Koh, Hyun Chul
- Issue Date
- May-2019
- Publisher
- SPRINGER HEIDELBERG
- Keywords
- Diquat (DQ); Autophagy; Apoptosis; P53; NF-kappa B; mTOR; MAPKs
- Citation
- ARCHIVES OF TOXICOLOGY, v.93, no.5, pp.1239 - 1253
- Indexed
- SCIE
SCOPUS
- Journal Title
- ARCHIVES OF TOXICOLOGY
- Volume
- 93
- Number
- 5
- Start Page
- 1239
- End Page
- 1253
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/147880
- DOI
- 10.1007/s00204-019-02424-7
- ISSN
- 0340-5761
- Abstract
- Autophagy and apoptosis are the major types of cell death in pesticide-induced neurotoxicity, and autophagy is known to play a role in cell protection by inhibiting apoptosis. In this study, we characterized the relationship between autophagy and apoptosis in diquat (DQ)-induced cell death and explored a novel pharmacotherapeutic approach involving autophagy regulation to prevent DQ neurotoxicity. DQ was cytotoxic to PC12 cells in a concentration-dependent manner, as shown by decreased cell viability and decreased dopamine (DA) levels. DQ-induced apoptosis was found in PC12 cells, as demonstrated by activation of caspase-3 and -9 and by nuclear condensation. By monitoring expression of microtubule-associated protein 1A/1B light chain 3B (LC3-II) and p62, DQ was found to induce autophagy. Exposure of PC12 cells to DQ led to the production of reactive oxygen species (ROS), and N-acetyl-cysteine (NAC) antioxidant effectively blocked both apoptosis and autophagy. Interestingly, DQ in PC12 cells showed increased p53 and NF-kappa B in a time-dependent manner; furthermore, pifithrin-alpha (PFT-alpha), a p53 inhibitor, downregulates the cytotoxicity of DQ, as shown by decreased LC3-II and cleaved caspase-3. SN50, an NF-kappa B inhibitor, results in diminished LC3-II, cleaved caspase-3, and p53. DQ induces mitogen-activated protein kinase (MAPK) signaling including ERK, JNK, and p38, which inhibit regulated apoptosis and autophagic cell death by controlling mTOR signaling. In addition, modulation of DQ-induced apoptosis in response to autophagy regulation was investigated. Pretreatment with rapamycin, an autophagy inducer, significantly enhanced the viability of DQ-exposed cells by alleviating DQ-induced apoptosis. Conversely, cell pretreatment with 3-methyladenine (3MA), an autophagy inhibitor increased DQ toxicity. Our results suggest that DQ-induced cytotoxicity is modified by autophagy regulation. Pharmacologic induction of autophagy may be a useful treatment strategy in neurodegenerative disorders.
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