title: The regulatory mechanism of 4-phenylbutyric acid against ER stress-induced autophagy in human gingival fibroblasts.
abstract: Endoplasmic reticulum (ER) stress is closely connected to autophagy. When cells are exposed to ER stress, cells exhibit enhanced protein degradation and form autophagosomes. In this study, we demonstrate that the chemical chaperone, 4-phenylbutyric acid (4-PBA), regulates ER stressinduced cell death and autophagy in human gingival fibroblasts. We found that 4-PBA protected cells against thapsigargin-induced apoptotic cell death but did not affect the reduced cell proliferation. ER stress induced by thapsigargin was alleviated by 4-PBA through the regulation of several ER stress-inducible, unfolded protein response related proteins including GRP78, GRP94, C/EBP homologous protein, phospho-eIF-2α, eIF-2α, phospho-JNK1 (p46) and phospho-JNK2/3 (p54), JNK1, IRE-1α, PERK, and sXBP-1. Compared with cells treated with thapsigargin alone, cells treated with both 4-PBA and thapsigargin showed lower levels of Beclin-1, LC-3II and autophagic vacuoles, indicating that 4-PBA also inhibited autophagy induced by ER stress. This study suggests that 4-PBA may be a potential therapeutic agent against ER stress-associated pathologic situations.
authors.affiliation: Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University, Jeonju, Chonbuk 561-180, Korea.
authors.forename: Do-Sung
authors.initials: DS
authors.lastname: Kim
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Ki Yon
authors.initials: KY
authors.lastname: Rhew
authors.forename: Hyo-Won
authors.initials: HW
authors.lastname: Oh
authors.forename: Hyun-Dae
authors.initials: HD
authors.lastname: Lim
authors.forename: Wan
authors.initials: W
authors.lastname: Lee
authors.forename: Han-Jung
authors.initials: HJ
authors.lastname: Chae
authors.forename: Hyung-Ryong
authors.initials: HR
authors.lastname: Kim
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005881:Gingiva / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010654:Phenylbutyrates / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000633:toxicity; D013997:Time Factors; D014162:Transfection; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D010654:Phenylbutyrates; D020011:Protective Agents; D019284:Thapsigargin; C075773:4-phenylbutyric acid