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NF-κB/mTOR-mediated autophagy can regulate diquat-induced apoptosis.
Arch Toxicol. 2019 05; 93(5):1239-1253.AT

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-κB in a time-dependent manner; furthermore, pifithrin-α (PFT-α), a p53 inhibitor, downregulates the cytotoxicity of DQ, as shown by decreased LC3-II and cleaved caspase-3. SN50, an NF-κB 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.

Authors+Show Affiliations

Department of Pharmacology, College of Medicine, Hanyang University, Sungdong-Gu, Haengdang-Dong 17, Seoul, 133-79, Republic of Korea.Department of Pharmacology, College of Medicine, Hanyang University, Sungdong-Gu, Haengdang-Dong 17, Seoul, 133-79, Republic of Korea. hckoh@hanyang.ac.kr. Hanyang Biomedical Research Institute, Sungdong-Gu, Haengdang- Dong 17, Seoul, 133-79, Republic of Korea. hckoh@hanyang.ac.kr. Graduate School of Biomedical Science and Engineering, Hanyang University, Sungdong-Gu, Haengdang-Dong 17, Seoul, 133-79, Republic of Korea. hckoh@hanyang.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30848314

Citation

Park, Aeri, and Hyun Chul Koh. "NF-κB/mTOR-mediated Autophagy Can Regulate Diquat-induced Apoptosis." Archives of Toxicology, vol. 93, no. 5, 2019, pp. 1239-1253.
Park A, Koh HC. NF-κB/mTOR-mediated autophagy can regulate diquat-induced apoptosis. Arch Toxicol. 2019;93(5):1239-1253.
Park, A., & Koh, H. C. (2019). NF-κB/mTOR-mediated autophagy can regulate diquat-induced apoptosis. Archives of Toxicology, 93(5), 1239-1253. https://doi.org/10.1007/s00204-019-02424-7
Park A, Koh HC. NF-κB/mTOR-mediated Autophagy Can Regulate Diquat-induced Apoptosis. Arch Toxicol. 2019;93(5):1239-1253. PubMed PMID: 30848314.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NF-κB/mTOR-mediated autophagy can regulate diquat-induced apoptosis. AU - Park,Aeri, AU - Koh,Hyun Chul, Y1 - 2019/03/08/ PY - 2018/08/22/received PY - 2019/03/04/accepted PY - 2019/3/9/pubmed PY - 2020/7/3/medline PY - 2019/3/9/entrez KW - Apoptosis KW - Autophagy KW - Diquat (DQ) KW - MAPKs KW - NF-κB KW - P53 KW - mTOR SP - 1239 EP - 1253 JF - Archives of toxicology JO - Arch. Toxicol. VL - 93 IS - 5 N2 - 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-κB in a time-dependent manner; furthermore, pifithrin-α (PFT-α), a p53 inhibitor, downregulates the cytotoxicity of DQ, as shown by decreased LC3-II and cleaved caspase-3. SN50, an NF-κB 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. SN - 1432-0738 UR - https://www.unboundmedicine.com/medline/citation/30848314/NF_κB/mTOR_mediated_autophagy_can_regulate_diquat_induced_apoptosis_ L2 - https://doi.org/10.1007/s00204-019-02424-7 DB - PRIME DP - Unbound Medicine ER -