title: Tris (1, 3-dichloro-2-propyl) phosphate induces apoptosis and autophagy in SH-SY5Y cells: Involvement of ROS-mediated AMPK/mTOR/ULK1 pathways.
abstract: Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP), an extensively used organophosphorus flame retardant, is frequently detected in the environment and biota. Recent studies have shown that TDCIPP has neurotoxic effects. We hypothesized that the neurotoxicity might occur via the induction of the apoptosis and autophagy pathways. In the present study, we investigated TDCIPP-induced apoptotic death and autophagy in SH-SY5Y cells. Treatment with TDCIPP induced increased reactive oxygen species (ROS) generation and cell apoptosis, as well as autophagy. The autophagy inhibitor 3-methyladenine (3-MA) markedly decreased the expression of the autophagy marker beclin-1, microtubule-associated protein light chain 3-II (LC3II), p62/sequestosome 1 (SQSTM1) degradation, and promoted apoptosis. Conversely, the autophagy inducer rapamycin (Rapa) alleviated TDCIPP-induced apoptosis and markedly increased the expression of the autophagy markers. Pretreatment with N-acetyl cysteine (NAC) eliminated the increased ROS generation, resulting in increased cell viability. For further examination of the signaling pathways involved in TDCIPP-induced autophagy, compound C, a pharmacological inhibitor of adenosine monophosphate activated protein kinase (AMPK) was used. Western blotting showed that compound C markedly reduced the expression of phospho-AMPK (p-AMPK) and phospho-Unc-51-like kinase 1 (p-ULK1), increased phospho-mammalian target of rapamycin (p-mTOR) expression, and decreased beclin-1 and LC3II expression. These results suggested that the AMPK/mTOR/ULK1 signaling pathway was involved in TDCIPP-induced autophagy. The antioxidant NAC antagonized TDCIPP-induced activation of AMPK and autophagy. Taken together, our findings provide the first evidence that TDCIPP promotes apoptosis and autophagy simultaneously and that this process involves the ROS-mediated AMPK/mTOR/ULK1 pathways. Lastly, the induction of autophagy is a protective mechanism against TDCIPP-induced apoptosis.
authors.affiliation: School of Resource and Environmental Science, Hubei Biomass-Resource Chemistry and Environmental Biotechnology Key Laboratory, Wuhan University, Wuhan 430079, China; State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Li
authors.affiliation: School of Resource and Environmental Science, Hubei Biomass-Resource Chemistry and Environmental Biotechnology Key Laboratory, Wuhan University, Wuhan 430079, China. Electronic address: zhoupj@whu.edu.cn.
authors.forename: Peijiang
authors.initials: P
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 16419, South Korea.
authors.forename: Jae-Seong
authors.initials: JS
authors.lastname: Lee
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China. Electronic address: bszhou@ihb.ac.cn.
authors.forename: Bingsheng
authors.initials: B
authors.lastname: Zhou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism*; D015153:Blotting, Western; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; C016805:tris(1,3-dichloro-2-propyl)phosphate; C546842:MTOR protein, human; D000071189:Autophagy-Related Protein-1 Homolog; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; D055372:AMP-Activated Protein Kinases
keywords: AMPK/mTOR/ULK1; Apoptosis; Autophagy; Neurotoxicity; ROS; Tris (1, 3-dichloro-2-propyl) phosphate