title: High and low LET radiation differentially induce normal tissue damage signals.
abstract: OBJECTIVE
  Radiotherapy using high linear energy transfer (LET) radiation is aimed at efficiently killing tumor cells while minimizing dose (biological effective) to normal tissues to prevent toxicity. It is well established that high LET radiation results in lower cell survival per absorbed dose than low LET radiation. However, whether various mechanisms involved in the development of normal tissue damage may be regulated differentially is not known. Therefore the aim of this study was to investigate whether two actions related to normal tissue toxicity, p53-induced apoptosis and expression of the profibrotic gene PAI-1 (plasminogen activator inhibitor 1), are differentially induced by high and low LET radiation.
  
  
  METHODS
  Cells were irradiated with high LET carbon ions or low LET photons. Cell survival assays were performed, profibrotic PAI-1 expression was monitored by quantitative polymerase chain reaction, and apoptosis was assayed by annexin V staining. Activation of p53 by phosphorylation at serine 315 and serine 37 was monitored by Western blotting. Transfections of plasmids expressing p53 mutated at serines 315 and 37 were used to test the requirement of these residues for apoptosis and expression of PAI-1.
  
  
  RESULTS
  As expected, cell survival was lower and induction of apoptosis was higher in high -LET irradiated cells. Interestingly, induction of the profibrotic PAI-1 gene was similar with high and low LET radiation. In agreement with this finding, phosphorylation of p53 at serine 315 involved in PAI-1 expression was similar with high and low LET radiation, whereas phosphorylation of p53 at serine 37, involved in apoptosis induction, was much higher after high LET irradiation.
  
  
  CONCLUSIONS
  Our results indicate that diverse mechanisms involved in the development of normal tissue damage may be differentially affected by high and low LET radiation. This may have consequences for the development and manifestation of normal tissue damage.
authors.affiliation: Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Niemantsverdriet
authors.forename: Marc-Jan
authors.initials: MJ
authors.lastname: van Goethem
authors.forename: Reinier
authors.initials: R
authors.lastname: Bron
authors.forename: Wytse
authors.initials: W
authors.lastname: Hogewerf
authors.forename: Sytze
authors.initials: S
authors.lastname: Brandenburg
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Langendijk
authors.forename: Peter
authors.initials: P
authors.lastname: van Luijk
authors.forename: Robert P
authors.initials: RP
authors.lastname: Coppes
mesh_terms: D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D002244:Carbon; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D015870:Gene Expression / Q000502:physiology / Q000528:radiation effects*; D016158:Genes, p53 / Q000502:physiology / Q000528:radiation effects*; D057809:HEK293 Cells; D006801:Humans; D018499:Linear Energy Transfer; D058958:Organs at Risk / Q000528:radiation effects*; D010766:Phosphorylation / Q000528:radiation effects; D017785:Photons; D010957:Plasmids / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011832:Radiation Injuries / Q000235:genetics*; D011882:Radiotherapy, High-Energy; D015533:Transcriptional Activation / Q000528:radiation effects
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D002244:Carbon