Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity
Open accessAbstract
We have previously shown that radiation increases HIF-1 activity in tumors, causing significant radioprotection of the tumor vasculature. The impact that HIF-1 activation has on overall tumor radiosensitivity, however, is unknown. We reveal here that HIF-1 plays an important role in determining tumor radioresponsiveness through regulating four distinct processes. By promoting ATP metabolism, proliferation, and p53 activation, HIF-1 has a radiosensitizing effect on tumors. Through stimulating endothelial cell survival, HIF-1 promotes tumor radioresistance. As a result, the net effect of HIF-1 blockade on tumor radioresponsiveness is highly dependent on treatment sequencing, with "radiation first" strategies being significantly more effective than the alternative. These data provide a strong rationale for pursuing sequence-specific combinations of HIF-1 blockade and conventional therapeutics.
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Silencing or pharmacological inhibition of HIF-1α can increase the anti-tumor effects of IR.
“Importantly, silencing or pharmacological inhibition of HIF-1α can increase the anti-tumor effects of IR (Zhang et al., 2004;Moeller et al., 2005;Harada et al., 2009;Harada et al., 2012).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Moeller et al., 2005
HIF-1α appears to exert both radiosensitizing and radioresistant effects.
“HIF-1α appears to exert both radiosensitizing (e.g., by promoting proliferation and p53-induced apoptosis) and radioresistant effects (via vascular radioprotection) (Moeller et al., 2005).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Moeller et al., 2005
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- Authors
- Moeller, B. J., Dreher, M. R., Rabbani, Z. N., Schroeder, T., 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
- 2005-08
- Volume
- 8
- Issue
- 2
- Pages
- 99-110
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W1971917580
- Cited by
- 374
- References
- 5
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 10 · 2023: 16 · 2022: 7 · 2021: 10 · 2020: 8 · 2019: 11 · 2018: 11 · 2017: 11 · 2016: 14 · 2015: 14 · 2014: 21 · 2013: 26 · 2012: 31
- FWCI
- 10.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA40355, R01CA040355)
- National Institute of Biomedical Imaging and Bioengineering (EB00188-01, R01EB000188)
- 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 › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
- Keywords
- HIF-1, tumor radiosensitivity, radioresistance (biology), p53 activation, ATP metabolism, cell proliferation, endothelial cell survival, treatment sequencing, combination therapy
- MeSH terms
- Adenosine Triphosphate, Animals, DNA-Binding Proteins, Endothelium, Vascular, Energy Metabolism, Humans, Neoplasms, Neovascularization, Pathologic, Nuclear Proteins, Radiation Tolerance, Transcription Factors, Tumor Suppressor Protein p53, Apoptosis, RNA Interference, Cell Proliferation, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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