title: 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.affiliation: Department of Biology Education, Daegu University, Gyungsan, Gyeongbuk 712-714, Republic of Korea.
authors.forename: Dong-Oh
authors.initials: DO
authors.lastname: Moon
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Asami
authors.forename: He
authors.initials: H
authors.lastname: Long
authors.forename: Jae Hyuk
authors.initials: JH
authors.lastname: Jang
authors.forename: Eon Young
authors.initials: EY
authors.lastname: Bae
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.forename: Chang-Hee
authors.initials: CH
authors.lastname: Kang
authors.forename: Jong Seog
authors.initials: JS
authors.lastname: Ahn
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014255:Trichothecenes / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D015852:Eukaryotic Initiation Factor-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D014255:Trichothecenes; D051742:Transcription Factor CHOP; C005348:muconomycin A