Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules.

Abstract	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.
Authors	Benjamin J Moeller, Yiting Cao, Chuan Y Li, Mark W Dewhirst
Journal	Cancer cell (Cancer Cell) Vol. 5 Issue 5 Pg. 429-41 (May 2004) ISSN: 1535-6108 [Print] United States
PMID	15144951 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Cesium Radioisotopes Cytokines DNA-Binding Proteins Free Radicals Hif1a protein, mouse Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Luminescent Proteins Nuclear Proteins Transcription Factors Green Fluorescent Proteins Oxygen
Topics	Animals Apoptosis (radiation effects) Cell Hypoxia (physiology) Cesium Radioisotopes Cytokines (metabolism) DNA-Binding Proteins (genetics, metabolism) Endothelium, Vascular (metabolism, radiation effects) Female Free Radicals Gamma Rays Gene Expression Regulation, Neoplastic Green Fluorescent Proteins Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Luminescent Proteins (metabolism) Mammary Neoplasms, Experimental (blood supply, metabolism, radiotherapy) Mice Neovascularization, Pathologic (metabolism) Nuclear Proteins (genetics, metabolism) Oxidative Stress (radiation effects) Oxygen (physiology) Protein Biosynthesis (radiation effects) Radiation Tolerance Transcription Factors

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!