Platycodin D induces reactive oxygen species-mediated apoptosis signal-regulating kinase 1 activation and endoplasmic reticulum stress response in human breast cancer cells.
Platycodin D (PD), a natural compound found in Platycodon grandiflorum, induces apoptotic cell death in various carcinoma cells. One mechanism of PD-mediated cell death is by activation of mitogen-activated protein kinases, as suggested in a recent report. In this study, we further examined upstream signal pathways and the relationship between these signals and reactive oxygen species (ROS). Using immunoblotting assays, we found that PD activated apoptosis signal-regulating kinase 1 (ASK1) through phosphorylation of ASK1 at threonine and dephosphorylation of ASK1 at serine. We also showed that PD caused activation of the endoplasmic reticulum (ER) stress response. This was supported by observations showing that treatment with PD induces phosphorylation of PKR-like ER kinase (PERK) and eukaryotic initiation factor 2 α (eIF 2α), up-regulating expression of glucose-regulated protein 78/immunoglobulin heavy chain binding protein (GRP78/Bip) and CCAAT/enhancer-binding protein homologous protein/growth arrest and DNA damage-inducible gene 153 (CHOP/GADD153) and activation of caspase-4. Furthermore, PD-induced ASK1 and ER stress responses were inhibited by the antioxidant N-acetyl-l-cysteine. These results suggest that ROS play a critical role for activation of ASK1 and ER stress in PD-treated cancer cells.
Biochemistry Laboratory, College of Pharmacy, Sookmyung Women's University, Seoul, Korea.
Ji Sun
JS
Yu
An Keun
AK
Kim
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D031238:Platycodon / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction; D014315:Triterpenes / Q000494:pharmacology*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D012503:Saponins; D014315:Triterpenes; C108953:platycodin D; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human