title: The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma.
abstract: Therapeutic resistance is a major barrier to improvement of outcomes for patients with glioblastoma. The endoplasmic reticulum stress response (ERSR) has been identified as a contributor to chemoresistance in glioblastoma; however the contributions of the ERSR to radioresistance have not been characterized. In this study we found that radiation can induce ER stress and downstream signaling associated with the ERSR. Induction of ER stress appears to be linked to changes in ROS balance secondary to irradiation. Furthermore, we observed global induction of genes downstream of the ERSR in irradiated glioblastoma. Knockdown of ATF6, a regulator of the ERSR, was sufficient to enhance radiation induced cell death. Also, we found that activation of ATF6 contributes to the radiation-induced upregulation of glucose regulated protein 78 (GRP78) and NOTCH1. Our results reveal ATF6 as a potential therapeutic target to enhance the efficacy of radiation therapy.
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.|Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: David Y A
authors.initials: DY
authors.lastname: Dadey
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Kapoor
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Arpine
authors.initials: A
authors.lastname: Khudanyan
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.|Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.|Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.|Hope Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Albert H
authors.initials: AH
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.|Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Thotala
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.|Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.|Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.|Hope Center, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000528:radiation effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000528:radiation effects*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1
keywords: ATF6; ER-stress; GRP78; glioblastoma; radioresistance