Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors
Open accessAbstract
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.
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ROS production later stabilizes the HIF-1α protein and increases expression of HIF-1α and its target genes.
“ROS production later stabilizes the HIF-1α protein and increases expression of HIF-1α and its target genes (Moeller et al., 2004;Dewhirst et al., 2008;Harada et al., 2009).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Moeller et al., 2004
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- Authors
- Moeller, B. J., Cao, Y., Li, C. Y., & Dewhirst, M. W.
- Affiliations
- Duke Medical Center (US)
- Corresponding author
- Dewhirst, Mark W
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2004-05
- Volume
- 5
- Issue
- 5
- Pages
- 429-441
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2030575063
- Cited by
- 996
- References
- 2
- Citations by year
- 2026: 21 · 2025: 30 · 2024: 34 · 2023: 46 · 2022: 33 · 2021: 50 · 2020: 51 · 2019: 44 · 2018: 35 · 2017: 42 · 2016: 71 · 2015: 42 · 2014: 61 · 2013: 63 · 2012: 49
- FWCI
- 17.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (40355)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- HIF-1, tumor radiosensitivity, tumor reoxygenation, stress granules, reactive oxygen species, cytokines, angiogenesis, vascular injury, radiotherapy response, tumor microenvironment
- MeSH terms
- Animals, Cesium Radioisotopes, DNA-Binding Proteins, Endothelium, Vascular, Female, Free Radicals, Gamma Rays, Luminescent Proteins, Mammary Neoplasms, Experimental, Neovascularization, Pathologic, Nuclear Proteins, Oxygen, Radiation Tolerance, Transcription Factors, Protein Biosynthesis, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Cytokines, Apoptosis, Oxidative Stress, Green Fluorescent Proteins, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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