title: The endoplasmic reticulum is a target organelle for trivalent dimethylarsinic acid (DMAIII)-induced cytotoxicity.
abstract: The purpose of present study was to characterize the endoplasmic reticulum stress and generation of ROS in rat liver RLC-16 cells by exposing to trivalent dimethylarsinous acid (DMAIII) and compared with that of trivalent arsenite (iAsIII) and monomethylarsonous acid (MMAIII). Protein kinase-like endoplasmic reticulum kinase (PERK) phosphorylation was significantly induced in cells exposed to DMAIII, while there was no change in phosphorylated PERK (P-PERK) detected in cells after exposure to iAsIII or MMAIII. The generation of reactive oxygen species (ROS) after DMAIII exposure was found to take place specifically in the endoplasmic reticulum (ER), while previous reports showed that ROS was generated in mitochondria following exposure to MMAIII. Meanwhile, cycloheximide (CHX) which is an inhibitor of protein biosynthesis strongly inhibited the DMAIII-induced intracellular ROS generation in the ER and the phosphorylation of PERK, suggesting the induction of ER stress probably occurs through the inhibition of the protein folding process. Activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) mRNA were induced by all three arsenic species, however, evidence suggested that they might be induced by different pathways in the case of iAsIII and MMAIII. In addition, ER resident molecular chaperone glucose-regulated protein78 (GRP78) was not affected by trivalent arsenicals, while it was induced in positive control only at high concentration (Thapsigargin;Tg), suggesting the GRP78 is less sensitive to low levels of ER stress. In summary, our findings demonstrate that the endoplasmic reticulum is a target organelle for DMAIII-induced cytotoxicity.
authors.affiliation: Department of Pharmacology, Toxicology, and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, and Zhejiang Hospital of Traditional Chinese Medicine, Hangzhou 310058, China. narenman@zju.edu.cn
authors.forename: Hua
authors.initials: H
authors.lastname: Naranmandura
authors.forename: Shi
authors.initials: S
authors.lastname: Xu
authors.forename: Shota
authors.initials: S
authors.lastname: Koike
authors.forename: Li Qiang
authors.initials: LQ
authors.lastname: Pan
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Yan Wei
authors.initials: YW
authors.lastname: Wang
authors.forename: Kanwal
authors.initials: K
authors.lastname: Rehman
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002101:Cacodylic Acid / Q000633:toxicity*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009942:Organometallic Compounds / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051701:Activating Transcription Factor 4; D018053:Arsenites; D002101:Cacodylic Acid; D006360:Heat-Shock Proteins; D009942:Organometallic Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497110:Atf4 protein, rat; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C406082:monomethylarsonous acid; C015001:arsenite