Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules.
Through a poorly understood mechanism, tumors respond to radiation by secreting cytokines capable of inhibiting apoptosis in endothelial cells, thereby diminishing treatment response by minimizing vascular damage. We reveal here that this pathway is governed by a major angiogenesis regulator, HIF-1. Following radiotherapy, tumor reoxygenation leads to: (1) nuclear accumulation of HIF-1 in response to reactive oxygen, and (2) enhanced translation of HIF-1-regulated transcripts secondary to stress granule depolymerization. The resulting increase in HIF-1-regulated cytokines enhances endothelial cell radioresistance. Inhibiting postradiation HIF-1 activation significantly increases tumor radiosensitivity as a result of enhanced vascular destruction. These data describe novel pathways contributing significantly to our understanding of HIF-1 regulation which may be major determinants of tumor radiosensitivity, potentially having high clinical relevance.
Moeller
Benjamin J
BJ
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Cao
Yiting
Y
Li
Chuan Y
CY
Dewhirst
Mark W
MW
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015687:Cell Hypoxia / Q000502:physiology; D002588:Cesium Radioisotopes; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D005609:Free Radicals; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008164:Luminescent Proteins / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000528:radiation effects*; D010100:Oxygen / Q000502:physiology*; D014176:Protein Biosynthesis / Q000528:radiation effects; D011836:Radiation Tolerance; D014157:Transcription Factors
D002588:Cesium Radioisotopes; D016207:Cytokines; D004268:DNA-Binding Proteins; D005609:Free Radicals; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008164:Luminescent Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D010100:Oxygen