title: HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism.
abstract: Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy. While hypoxia increases tumor cell survival after radiation exposure because there is less oxygen to oxidize damaged DNA, it remains unclear whether signaling pathways triggered by hypoxia contribute to radiation resistance. For example, intratumoral hypoxia can increase hypoxia inducible factor 1 alpha (HIF-1α), which may regulate pathways that contribute to radiation sensitization or radiation resistance. To clarify the role of HIF-1α in regulating tumor response to radiation, we generated a novel genetically engineered mouse model of soft tissue sarcoma with an intact or deleted HIF-1α. Deletion of HIF-1α sensitized primary sarcomas to radiation exposure in vivo. Moreover, cell lines derived from primary sarcomas lacking HIF-1α, or in which HIF-1α was knocked down, had decreased clonogenic survival in vitro, demonstrating that HIF-1α can promote radiation resistance in a cell autonomous manner. In HIF-1α-intact and -deleted sarcoma cells, radiation-induced reactive oxygen species, DNA damage repair and activation of autophagy were similar. However, sarcoma cells lacking HIF-1α had impaired mitochondrial biogenesis and metabolic response after irradiation, which might contribute to radiation resistance. These results show that HIF-1α promotes radiation resistance in a cell autonomous manner.
authors.affiliation: a  Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of.
authors.forename: Minsi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: b  Radiation Oncology.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: b  Radiation Oncology.
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: b  Radiation Oncology.
authors.forename: Mohit
authors.initials: M
authors.lastname: Sachdeva
authors.affiliation: b  Radiation Oncology.
authors.forename: Hooney
authors.initials: H
authors.lastname: Min
authors.affiliation: c  Pathology.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Cardona
authors.affiliation: f  Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts; and.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: DeLaney
authors.affiliation: b  Radiation Oncology.
authors.forename: Tracy
authors.initials: T
authors.lastname: Han
authors.affiliation: b  Radiation Oncology.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: b  Radiation Oncology.
authors.forename: Lixia
authors.initials: L
authors.lastname: Luo
authors.affiliation: g  Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: a  Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of.
authors.forename: Ki
authors.initials: K
authors.lastname: Lui
authors.affiliation: a  Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Nichols
authors.affiliation: a  Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of.|g  Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: a  Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of.|d  Pediatrics and.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kastan
authors.affiliation: a  Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of.|e  Immunology, Duke University Medical Center, Durham, North Carolina;
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Rathmell
authors.affiliation: b  Radiation Oncology.|c  Pathology.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.affiliation: a  Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of.|b  Radiation Oncology.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects; D053142:Mitochondrial Size / Q000235:genetics / Q000528:radiation effects; D011836:Radiation Tolerance / Q000235:genetics / Q000528:radiation effects; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit