title: Endoplasmic Reticulum Stress Protein GRP78 Modulates Lipid Metabolism to Control Drug Sensitivity and Antitumor Immunity in Breast Cancer.
abstract: The unfolded protein response is an endoplasmic reticulum stress pathway mediated by the protein chaperone glucose regulated-protein 78 (GRP78). Metabolic analysis of breast cancer cells shows that GRP78 silencing increases the intracellular concentrations of essential polyunsaturated fats, including linoleic acid. Accumulation of fatty acids is due to an inhibition of mitochondrial fatty acid transport, resulting in a reduction of fatty acid oxidation. These data suggest a novel role of GRP78-mediating cellular metabolism. We validated the effect of GRP78-regulated metabolite changes by treating tumor-bearing mice with tamoxifen and/or linoleic acid. Tumors treated with linoleic acid plus tamoxifen exhibited reduced tumor area and tumor weight. Inhibition of either GRP78 or linoleic acid treatment increased MCP-1 serum levels, decreased CD47 expression, and increased macrophage infiltration, suggesting a novel role for GRP78 in regulating innate immunity. GRP78 control of fatty acid oxidation may represent a new homeostatic function for GRP78. Cancer Res; 76(19); 5657-70. ©2016 AACR.
authors.affiliation: Department of Surgery and Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC. klcook@wakehealth.edu.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Cook
authors.affiliation: Department of Surgery and Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: David R
authors.initials: DR
authors.lastname: Soto-Pantoja
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Pamela A G
authors.initials: PA
authors.lastname: Clarke
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: M Idalia
authors.initials: MI
authors.lastname: Cruz
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Alan
authors.initials: A
authors.lastname: Zwart
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Anni
authors.initials: A
authors.lastname: Wärri
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Leena
authors.initials: L
authors.lastname: Hilakivi-Clarke
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
authors.affiliation: Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D051928:CD47 Antigen / Q000502:physiology; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D050356:Lipid Metabolism; D055432:Metabolomics; D051379:Mice; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D005227:Fatty Acids; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D017382:Reactive Oxygen Species