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

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

Department of Biology Education, Daegu University, Gyungsan, Gyeongbuk 712-714, Republic of Korea.

Toxicology in vitro : an international journal published in association with BIBRA 2013 Feb

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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. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

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. Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2α/CHOP-dependent manner. Toxicology in vitro : an international journal published in association with BIBRA. 2013 Feb;27(1):257-63