title: Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor 5 (DR5) by zerumbone and celecoxib.
abstract: Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that triggers cell death upon binding to its ligand, TNF-related apoptosis-inducing ligand (TRAIL), and a combination of TRAIL and agents that increase the expression of DR5 is expected to be a novel anticancer therapy. In this report, we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells. Both agents activated PERK-eIF2α kinases and induced the expression of activating transcription factor 4 (ATF4)-CCAAT enhancer-binding protein (C/EBP) homologous protein, which were remarkably suppressed by reactive oxygen species scavengers. In the absence of ATF3, the induction of DR5 mRNA and protein was abrogated significantly, and this was associated with reduced cell death by cotreatment of TRAIL with ZER or CCB. By contrast, exogenous expression of ATF3 caused a more rapid and elevated expression of DR5, resulting in enhanced sensitivity to apoptotic cell death by TRAIL/ZER or TRAIL/CCB. A reporter assay demonstrated that at least two ATF/cAMP response element motifs as well as C/EBP homologous protein motif at the proximal region of the human DR5 gene promoter were required for ZER-induced DR5 gene transcription. Taken together, our results provide novel insights into the role of ATF3 as an essential transcription factor for p53-independent DR5 induction upon both ZER and CCB treatment, and this may be a useful biomarker for TRAIL-based anticancer therapy.
authors.affiliation: From the Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan, the Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan, and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Edagawa
authors.affiliation: From the Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kawauchi
authors.affiliation: From the Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Hirata
authors.affiliation: From the Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Goshima
authors.affiliation: From the Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.affiliation: the Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan, and.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: the Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
authors.affiliation: the Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan, and.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.affiliation: From the Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan, kita.bgen@mri.tmd.ac.jp.
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Kitajima
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D000068579:Celecoxib; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006801:Humans; D011401:Promoter Regions, Genetic; D011720:Pyrazoles / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D017931:DNA Primers; D011720:Pyrazoles; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D012717:Sesquiterpenes; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C403304:zerumbone; D000068579:Celecoxib
keywords: ATF3; Apoptosis; Cancer Therapy; Colon Cancer; DR5; ER Stress; Gene Regulation; Reactive Oxygen Species (ROS); p53-independent