Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2α/CHOP-dependent manner.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. However, resistance to TRAIL in some cancers remains a current problem in recent. The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis. Therefore, we examined whether verrucarin A (VA) sensitize TRAIL-induced apoptosis in cancer cells by induction of ER stress. We first found that VA induces a major molecule of ER stress, CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 induction and subsequently increases TRAIL-induced cleavage of caspases and PARP in TRAIL-resistant Hep3B cells. Importantly, the transient knockdown using siRNA for CHOP abrogated VA-induced DR5 expression and attenuated TRAIL-induced apoptosis. Treatment with VA also increased the levels of phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), which is a common cellular response of ER stress. Furthermore, salubrinal, a specific eIF2α phosphorylation-inducing agent, increased CHOP and DR5 expression in the presence of VA. In contrast, transfection of mutant-eIF2α significantly reversed VA-induced apoptosis with downregulation of CHOP-dependent DR5 expression. Therefore, VA-induced eIF2α phosphorylation seemed to be important for CHOP and DR5 upregulation and TRAIL-induced apoptosis. In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress. We concluded that VA triggers TRAIL-induced apoptosis by eIF2α/CHOP-dependent DR5 induction via ROS generation.

• Authors: Dong-Oh Moon, Yukihiro Asami, He Long, Jae Hyuk Jang, Eon Young Bae, Bo Yeon Kim, Yung Hyun Choi, Chang-Hee Kang, Jong Seog Ahn, Gi-Young Kim
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 27 Issue 1 Pg. 257-63 (Feb 2013) ISSN: 1879-3177 [Electronic] England
• PMID: 22982206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• DDIT3 protein, human
• Eukaryotic Initiation Factor-2
• RNA, Small Interfering
• Reactive Oxygen Species
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• Trichothecenes
• Transcription Factor CHOP
• muconomycin A

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Eukaryotic Initiation Factor-2 (metabolism)
• Humans
• RNA, Small Interfering (genetics)
• Reactive Oxygen Species (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (biosynthesis, genetics)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Transcription Factor CHOP (genetics, metabolism)
• Trichothecenes (pharmacology)
• Up-Regulation