title: CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation.
abstract: Modulating tissue responses to stress is an important therapeutic objective. Oxidative and genotoxic stresses caused by ionizing radiation are detrimental to healthy tissues but beneficial for treatment of cancer. CD47 is a signaling receptor for thrombospondin-1 and an attractive therapeutic target because blocking CD47 signaling protects normal tissues while sensitizing tumors to ionizing radiation. Here we utilized a metabolomic approach to define molecular mechanisms underlying this radioprotective activity. CD47-deficient cells and cd47-null mice exhibited global advantages in preserving metabolite levels after irradiation. Metabolic pathways required for controlling oxidative stress and mediating DNA repair were enhanced. Some cellular energetics pathways differed basally in CD47-deficient cells, and the global declines in the glycolytic and tricarboxylic acid cycle metabolites characteristic of normal cell and tissue responses to irradiation were prevented in the absence of CD47. Thus, CD47 mediates signaling from the extracellular matrix that coordinately regulates basal metabolism and cytoprotective responses to radiation injury.
authors: From the Laboratory of Pathology and Paradigm Shift Therapeutics, Rockville, Maryland 20852, and.
authors: Thomas W
authors: http://orcid.org/0000-0001-8645-2785
authors: TW
authors: Miller
authors: From the Laboratory of Pathology and Departments of Cancer Biology and Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157 dsotopan@wakehealth.edu.
authors: David R
authors: DR
authors: Soto-Pantoja
authors: From the Laboratory of Pathology and.
authors: Anthony L
authors: AL
authors: Schwartz
authors: From the Laboratory of Pathology and.
authors: John M
authors: JM
authors: Sipes
authors: Radiation Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors: William G
authors: WG
authors: DeGraff
authors: Radiation Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors: Lisa A
authors: LA
authors: Ridnour
authors: Radiation Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors: David A
authors: DA
authors: Wink
authors: From the Laboratory of Pathology and droberts@helix.nih.gov.
authors: David D
authors: http://orcid.org/0000-0002-2481-2981
authors: DD
authors: Roberts
mesh_terms: D000818:Animals; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D002952:Citric Acid Cycle / Q000528:radiation effects; D004734:Energy Metabolism / Q000528:radiation effects; D017353:Gene Deletion; D006706:Homeostasis / Q000528:radiation effects; D006801:Humans; D019169:Jurkat Cells; D053858:Metabolic Networks and Pathways / Q000528:radiation effects*; D055432:Metabolomics; D051379:Mice; D009711:Nucleotides / Q000096:biosynthesis; D018384:Oxidative Stress / Q000528:radiation effects; D010427:Pentose Phosphate Pathway / Q000528:radiation effects; D011836:Radiation Tolerance
chemical_list: D051928:CD47 Antigen; D009711:Nucleotides
keywords: CD47; energetics; glucose metabolism; nucleoside/nucleotide metabolism; oxidative stress; radiation biology; radioprotection