RRC ID 37601
Author Iwao C, Shidoji Y.
Title Polyunsaturated Branched-Chain Fatty Acid Geranylgeranoic Acid Induces Unfolded Protein Response in Human Hepatoma Cells.
Journal PLoS ONE
Abstract The acyclic diterpenoid acid geranylgeranoic acid (GGA) has been reported to induce autophagic cell death in several human hepatoma-derived cell lines; however, the molecular mechanism for this remains unknown. In the present study, several diterpenoids were examined for ability to induce XBP1 splicing and/or lipotoxicity for human hepatoma cell lines. Here we show that three groups of diterpenoids emerged: 1) GGA, 2,3-dihydro GGA and 9-cis retinoic acid induce cell death and XBP1 splicing; 2) all-trans retinoic acid induces XBP1 splicing but little cell death; and 3) phytanic acid, phytenic acid and geranylgeraniol induce neither cell death nor XBP1 splicing. GGA-induced ER stress/ unfolded protein response (UPR) and its lipotoxicity were both blocked by co-treatment with oleic acid. The blocking activity of oleic acid for GGA-induced XBP1 splicing was not attenuated by methylation of oleic acid. These findings strongly suggest that GGA at micromolar concentrations induces the so-called lipid-induced ER stress response/UPR, which is oleate-suppressive, and shows its lipotoxicity in human hepatoma cells.
Volume 10(7)
Pages e0132761
Published 2015
DOI 10.1371/journal.pone.0132761
PII PONE-D-15-08199
PMID 26186544
PMC PMC4506074
MeSH Carcinoma, Hepatocellular / pathology* Cell Death / drug effects Cell Line, Tumor Cell Nucleus / drug effects Cell Nucleus / metabolism DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Diterpenes / chemistry Diterpenes / pharmacology* Fatty Acids, Unsaturated / chemistry Fatty Acids, Unsaturated / pharmacology* Humans Inhibitory Concentration 50 Liver Neoplasms / pathology* Microtubule-Associated Proteins / metabolism Oleic Acid / pharmacology Palmitates / pharmacology RNA Splicing / drug effects RNA Splicing / genetics Regulatory Factor X Transcription Factors Transcription Factors / genetics Transcription Factors / metabolism Unfolded Protein Response / drug effects* X-Box Binding Protein 1
IF 2.766
Times Cited 1
Human and Animal Cells