RRC ID 67747
Author Namba T, Kodama R.
Title Avarol induces apoptosis in pancreatic ductal adenocarcinoma cells by activating PERK-eIF2α-CHOP signaling.
Journal Mar Drugs
Abstract Avarol is a sesquiterpenoid hydroquinone with potent cytotoxicity. Although resolving endoplasmic reticulum (ER) stress is essential for intracellular homeostasis, erratic or excessive ER stress can lead to apoptosis. Here, we reported that avarol selectively induces cell death in pancreatic ductal adenocarcinomas (PDAC), which are difficult to treat owing to the availability of few chemotherapeutic agents. Analyses of the molecular mechanisms of avarol-induced apoptosis indicated upregulation of ER stress marker BiP and ER stress-dependent apoptosis inducer CHOP in PDAC cells but not in normal cells, suggesting that avarol selectively induces ER stress responses. We also showed that avarol activated the PERK-eIF2α pathway but did not affect the IRE1 and ATF6 pathways. Moreover, CHOP downregulation was significantly suppressed by avarol-induced apoptosis. Thus, the PERK-eIF2α-CHOP signaling pathway may be a novel molecular mechanism of avarol-induced apoptosis. The present data indicate that avarol has potential as a chemotherapeutic agent for PDAC and induces apoptosis by activating the PERK-eIF2α pathway.
Volume 13(4)
Pages 2376-89
Published 2015-4-16
DOI 10.3390/md13042376
PII md13042376
PMID 25894488
PMC PMC4413216
MeSH Animals Antineoplastic Agents / adverse effects Antineoplastic Agents / pharmacology* Apoptosis / drug effects Biomarkers / metabolism Carcinoma, Pancreatic Ductal / drug therapy* Carcinoma, Pancreatic Ductal / metabolism Cell Line Cell Line, Tumor Dysidea / chemistry Endoplasmic Reticulum Chaperone BiP Endoplasmic Reticulum Stress / drug effects Eukaryotic Initiation Factor-2 / agonists Eukaryotic Initiation Factor-2 / metabolism Gene Expression Regulation, Neoplastic / drug effects Heat-Shock Proteins / agonists Heat-Shock Proteins / genetics Heat-Shock Proteins / metabolism Humans Inhibitory Concentration 50 Neoplasm Proteins / agonists Neoplasm Proteins / antagonists & inhibitors Neoplasm Proteins / genetics Neoplasm Proteins / metabolism Pancreatic Neoplasms / drug therapy* Pancreatic Neoplasms / metabolism RNA Interference Sesquiterpenes / adverse effects Sesquiterpenes / pharmacology* Signal Transduction / drug effects* Transcription Factor CHOP / agonists* Transcription Factor CHOP / antagonists & inhibitors Transcription Factor CHOP / genetics Transcription Factor CHOP / metabolism Up-Regulation / drug effects eIF-2 Kinase / chemistry eIF-2 Kinase / metabolism*
IF 4.073
Human and Animal Cells PK-1(RCB1972) KLM-1(RCB2138)