title: TRAIL-Induced Caspase Activation Is a Prerequisite for Activation of the Endoplasmic Reticulum Stress-Induced Signal Transduction Pathways.
abstract: It is well known that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis can be initially triggered by surface death receptors (the extrinsic pathway) and subsequently amplified through mitochondrial dysfunction (the intrinsic pathway). However, little is known about signaling pathways activated by the TRAIL-induced endoplasmic reticulum (ER) stress response. In this study, we report that TRAIL-induced apoptosis is associated with the endoplasmic reticulum (ER) stress response. Human colorectal carcinoma HCT116 cells were treated with TRAIL and the ER stress-induced signal transduction pathway was investigated. During TRAIL treatment, expression of ER stress marker genes, in particular the BiP (binding immunoglobulin protein) gene, was increased and activation of the PERK (PKR-like ER kinase)-eIF2α (eukaryotic initiation factor 2α)-ATF4 (activating transcription factor 4)-CHOP (CCAAT-enhancer-binding protein homologous protein) apoptotic signal transduction pathway occurred. Experimental data from use of a siRNA (small interfering RNA) technique, caspase inhibitor, and caspase-3-deficient cell line revealed that TRAIL-induced caspase activation is a prerequisite for the TRAIL-induced ER stress response. TRAIL-induced ER stress was triggered by caspase-8-mediated cleavage of BAP31 (B cell receptor-associated protein 31). The involvement of the proapoptotic PERK-CHOP pathway in TRAIL-induced apoptosis was verified by using a PERK knockout (PERK(-/-)) mouse embryo fibroblast (MEF) cell line and a CHOP(-/-) MEF cell line. These results suggest that TRAIL-induced the activation of ER stress response plays a role in TRAIL-induced apoptotic death.
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.|Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Dae-Hee
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh 15261, Pennsylvania.|Protein Metabolism Medical Research Center and Department of Biomedical Science, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Ki Sa
authors.initials: KS
authors.lastname: Sung
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.
authors.forename: Zong Sheng
authors.initials: ZS
authors.lastname: Guo
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.
authors.forename: William Taehyung
authors.initials: WT
authors.lastname: Kwon
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.affiliation: Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sang Cheul
authors.initials: SC
authors.lastname: Oh
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Science, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.|Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh 15213, Pennsylvania.
authors.forename: Yong J
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D053181:Caspase 8; D008565:Membrane Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C091247:BCAP31 protein, human
keywords: CLEAVAGE OF BAP31; PERK-eIF2α-ATF4-CHOP SIGNALS; TRAIL-INDUCED CASPASE-8 ACTIVATION; TRAIL-INDUCED ER STRESS