title: Salubrinal protects against Clostridium difficile toxin B-induced CT26 cell death.
abstract: Clostridium difficile (C. difficile) is considered to be the major cause of the antibiotic-associated diarrhea and pseudomembranous colitis in animals and humans. The prevalence of C. difficile infections (CDI) has been increasing since 2000. Two exotoxins of C. difficile, Toxin A (TcdA) and Toxin B (TcdB), are the main virulence factors of CDI, which can induce glucosylation of Rho GTPases in host cytosol, leading to cell morphological changes, cell apoptosis, and cell death. The mechanism of TcdB-induced cell death has been investigated for decades, but it is still not completely understood. It has been reported that TcdB induces endoplasmic reticulum stress via PERK-eIF2α signaling pathway in CT26 cell line (BALB/C mouse colon tumor cells). In this study, we found that salubrinal, a selective inhibitor of eIF2α dephosphorylation, efficiently protects CT26 cell line against TcdB-induced cell death and tried to explore the mechanism underlying in this protective effect. Our results demonstrated that salubrinal protects CT26 cells from TcdB-mediated cytotoxic and cytopathic effect, inhibits apoptosis and death of the toxin-exposed cells via caspase-9-dependent pathway, eIF2α signaling pathway, and autophagy. These findings will be helpful for the development of CDI therapies.
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Chen
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Sun
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Huawei
authors.initials: H
authors.lastname: Gu
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ma
authors.affiliation: School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Jufang
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001426:Bacterial Proteins / Q000633:toxicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015151:Immunoblotting; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009479:Neuropeptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D009479:Neuropeptides; D020011:Protective Agents; C484602:Rac1 protein, mouse; C496827:salubrinal; C031815:toxB protein, Clostridium difficile; D053453:Caspase 9; D020830:rac1 GTP-Binding Protein; D013890:Thiourea
keywords: TcdB; apoptosis; autophagy; cell death; salubrinal