PMID- 27003169 OWN - NLM STAT- MEDLINE DCOM- 20160802 LR - 20211203 IS - 0895-3988 (Print) IS - 0895-3988 (Linking) VI - 29 IP - 2 DP - 2016 Feb TI - Cadmium Activates Reactive Oxygen Species-dependent AKT/mTOR and Mitochondrial Apoptotic Pathways in Neuronal Cells. PG - 117-26 LID - 10.3967/bes2016.013 [doi] AB - OBJECTIVE: To examine the role of Cd-induced reactive oxygen species (ROS) generation in the apoptosis of neuronal cells. METHODS: Neuronal cells (primary rat cerebral cortical neurons and PC12 cells) were incubated with or without Cd post-pretreatment with rapamycin (Rap) or N-acetyl-L-cysteine (NAC). Cell viability was determined by MTT assay, apoptosis was examined using flow cytometry and fluorescence microscopy, and the activation of phosphoinositide 3'-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and mitochondrial apoptotic pathways were measured by western blotting or immunofluorescence assays. RESULTS: Cd-induced activation of Akt/mTOR signaling, including Akt, mTOR, p70 S6 kinase (p70 S6K), and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). Rap, an mTOR inhibitor and NAC, a ROS scavenger, blocked Cd-induced activation of Akt/mTOR signaling and apoptosis of neuronal cells. Furthermore, NAC blocked the decrease of B-cell lymphoma 2/Bcl-2 associated X protein (Bcl-2/Bax) ratio, release of cytochrome c, cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (Endo G). CONCLUSION: Cd-induced ROS generation activates Akt/mTOR and mitochondrial pathways, leading to apoptosis of neuronal cells. Our findings suggest that mTOR inhibitors or antioxidants have potential for preventing Cd-induced neurodegenerative diseases. CI - Copyright (c) 2016 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved. FAU - Yuan, Yan AU - Yuan Y AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. FAU - Wang, Yi AU - Wang Y AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. FAU - Hu, Fei Fei AU - Hu FF AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. FAU - Jiang, Chen Yang AU - Jiang CY AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. FAU - Zhang, Ya Jing AU - Zhang YJ AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. FAU - Yang, Jin Long AU - Yang JL AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. FAU - Zhao, Shi Wen AU - Zhao SW AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. FAU - Gu, Jian Hong AU - Gu JH AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. FAU - Liu, Xue Zhong AU - Liu XZ AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. FAU - Bian, Jian Chun AU - Bian JC AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. FAU - Liu, Zong Ping AU - Liu ZP AD - College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, Jiangsu, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - China TA - Biomed Environ Sci JT - Biomedical and environmental sciences : BES JID - 8909524 RN - 0 (Reactive Oxygen Species) RN - 00BH33GNGH (Cadmium) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.22.- (Caspases) SB - IM MH - Animals MH - Apoptosis/*drug effects MH - Cadmium/*toxicity MH - Caspases/metabolism MH - Mitochondria/drug effects MH - Neurons/*drug effects MH - PC12 Cells MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Reactive Oxygen Species/*metabolism MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/metabolism OTO - NOTNLM OT - AKT/mTOR pathway OT - Apoptosis OT - Cadmium OT - Mitochondrial apoptotic pathway OT - PC12 cells OT - Primary rat cerebral cortical neurons EDAT- 2016/03/24 06:00 MHDA- 2016/08/03 06:00 CRDT- 2016/03/23 06:00 PHST- 2015/09/16 00:00 [received] PHST- 2016/01/26 00:00 [accepted] PHST- 2016/03/23 06:00 [entrez] PHST- 2016/03/24 06:00 [pubmed] PHST- 2016/08/03 06:00 [medline] AID - S0895-3988(16)30023-X [pii] AID - 10.3967/bes2016.013 [doi] PST - ppublish SO - Biomed Environ Sci. 2016 Feb;29(2):117-26. doi: 10.3967/bes2016.013.