title: Stabilisation and knockdown of HIF--two distinct ways comparably important in radiotherapy.
abstract: BACKGROUND
  Radiotherapy is one of the most widely used treatments for cancer. The benefit of radiation is known to be negatively affected by tumor hypoxia and the expression of hypoxia-inducible factors (HIF), respectively. HIF-1α/ β and HIF-2α/ β are transcriptional activators of oxygen-regulated genes. The aim of the study was to examine cell type-specific effects of HIF-1α and -2α knockdown or oxygen-independent HIF-stabilisation on radiosensitivity.
  
  
  METHODS
  Herein, we treated four different wildtype and HIF-1α- or HIF-2α-deficient human cancer cell lines, cultured under normoxic or hypoxic conditions, with ionising radiation in doses from 2 to 6 Gy and examined clonogenic survival. Furthermore, the cells were partly preincubated with a HIF-stabiliser (di-tert-butyroyl-oxymethyl-2,4-pyridine-dicarboxylate, (t)Bu-2,4-PDC).
  
  
  RESULTS
  The results show that both hypoxia exposure and treatment with (t)Bu-2,4-PDC increased the radioresistance of human cancer cells. The HIF-mediated decrease of radioresponsiveness induced by the chemical stabiliser emerged to be as strong as the one caused by hypoxia. Clonogenic survival assays furthermore revealed that HIF-1 expression enhanced resistance to radiation, whereas knocking-down HIF-1 increased the sensitivity to radiation under normoxic as well as under hypoxic conditions.
  
  
  CONCLUSIONS
  These data extend previous observations of HIF-1α and broaden the view by showing HIF-2α inverse correlation between HIF expression and prognosis for the outcome of radiotherapy.
authors.affiliation: Department of Physiology, Center for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Ströfer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jelkmann
authors.forename: Eric
authors.initials: E
authors.lastname: Metzen
authors.forename: Ulf
authors.initials: U
authors.lastname: Brockmeier
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dunst
authors.forename: Reinhard
authors.initials: R
authors.lastname: Depping
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000532:radiotherapy; D010875:Pipecolic Acids / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010875:Pipecolic Acids; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1; C041091:2,4-piperidinedicarboxylic acid