Radiation therapy generates platelet-activating factor agonists

Oncotarget. 2016 Apr 12;7(15):20788-800. doi: 10.18632/oncotarget.7878.


Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens.

Keywords: antioxidants; cyclooxygenase type 2 enzyme; oxidized glycerophosphocholines; platelet-activating factor; radiation therapy.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Female
  • Humans
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / pathology
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Oxidative Stress
  • Platelet Activating Factor / agonists*
  • Platelet Membrane Glycoproteins / agonists*
  • Platelet Membrane Glycoproteins / physiology
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / physiology
  • Signal Transduction
  • Skin Neoplasms / immunology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / secondary
  • Skin Neoplasms / therapy*
  • Tumor Cells, Cultured
  • Ultraviolet Rays*
  • Xenograft Model Antitumor Assays


  • Antioxidants
  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Receptors, G-Protein-Coupled
  • platelet activating factor receptor