Avarol induces apoptosis in pancreatic ductal adenocarcinoma cells by activating PERK-eIF2α-CHOP signaling.

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.

• Authors: Takushi Namba, Rika Kodama
• Journal: Marine drugs (Mar Drugs) Vol. 13 Issue 4 Pg. 2376-89 (Apr 16 2015) ISSN: 1660-3397 [Electronic] Switzerland
• PMID: 25894488 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers
• DDIT3 protein, human
• Endoplasmic Reticulum Chaperone BiP
• Eukaryotic Initiation Factor-2
• Heat-Shock Proteins
• Neoplasm Proteins
• Sesquiterpenes
• Transcription Factor CHOP
• EIF2AK3 protein, human
• eIF-2 Kinase
• avarol

Topics

• Animals
• Antineoplastic Agents (adverse effects, pharmacology)
• Apoptosis (drug effects)
• Biomarkers (metabolism)
• Carcinoma, Pancreatic Ductal (drug therapy, metabolism)
• Cell Line
• Cell Line, Tumor
• Dysidea (chemistry)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Eukaryotic Initiation Factor-2 (agonists, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Heat-Shock Proteins (agonists, genetics, metabolism)
• Humans
• Inhibitory Concentration 50
• Neoplasm Proteins (agonists, antagonists & inhibitors, genetics, metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism)
• RNA Interference
• Sesquiterpenes (adverse effects, pharmacology)
• Signal Transduction (drug effects)
• Transcription Factor CHOP (agonists, antagonists & inhibitors, genetics, metabolism)
• Up-Regulation (drug effects)
• eIF-2 Kinase (chemistry, metabolism)