The hypoxia-inducible factor-1α is a negative factor for tumor therapy
Open accessAbstract
Tumor hypoxia negatively regulates cell growth and causes a more malignant phenotype by increasing the expression of genes encoding angiogenic, metabolic and metastatic factors. Of clinical importance, insufficient tumor oxygenation affects the efficiency of chemotherapy and radiotherapy by poorly understood mechanisms. The hypoxia-inducible factor (HIF)-1 is a master transcriptional activator of oxygen-regulated genes and HIF-1 is constitutively upregulated in several tumor types. HIF-1 might thus be implicated in tumor therapy resistance. We found that transformed mouse embryonic fibroblasts deficient for HIF-1alpha are more susceptible to the treatment with carboplatin, etoposide and ionizing radiation than wild-type cells. Increased cell death in HIF-1alpha-deficient cells was because of apoptosis and did not involve p53 induction. Tumor chemotherapy of experimental fibrosarcoma in immunocompromised mice with carboplatin and etoposide confirmed the enhanced susceptibility of HIF-1alpha-deficient cells. Agents that did not cause DNA double-strand breaks, such as DNA-synthesis inhibitors or a DNA single-strand break-causing agent equally impaired cell growth, independent of the HIF-1alpha genotype. Functional repair of a fragmented reporter gene was decreased in HIF-1alpha-deficient cells. Thus, hypoxia-independent basal HIF-1alpha expression in tumor cells, as known from untransformed embryonic stem cells, is sufficient to induce target gene expression, probably including…
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HIF1/2 inhibitors might be effective in combination with conventional chemotherapy.
“Taken together, these data on the role of HIFs in therapeutic resistance suggest that HIF1/2 inhibitors might be effective in combination with conventional chemotherapy (Unruh et al., 2003;Erler et al., 2004;Brown et al., 2006;Nardinocchi et al., 2009;Roberts et al., 2009;He et al., 2012;Zhao et al., 2014).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Unruh et al., 2003
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- Authors
- Unruh, A., Ressel, A., Mohamed, H. G., Johnson, R. S., Nadrowitz, R., Richter, E., Katschinski, D. M., & Wenger, R. H.
- Affiliations
- University of Lübeck (DE)
- University of California San Diego (US)
- Martin Luther University Halle-Wittenberg (DE)
- Leipzig University (DE)
- Corresponding author
- Wenger, Roland H
- Venue
- Oncogene
- Published
- 2003-05-22
- Volume
- 22
- Issue
- 21
- Pages
- 3213-3220
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W1976880272
- Cited by
- 334
- References
- 7
- Citations by year
- 2025: 8 · 2024: 4 · 2023: 10 · 2022: 4 · 2021: 15 · 2020: 7 · 2019: 7 · 2018: 7 · 2017: 14 · 2016: 17 · 2015: 18 · 2014: 16 · 2013: 12 · 2012: 18
- FWCI
- 9.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.zora.uzh.ch
- Licence
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Keywords
- hypoxia-inducible factor-1α, tumor hypoxia, chemoresistance, radiotherapy resistance, carboplatin, etoposide, ionizing radiation, apoptosis, DNA double-strand break repair, DNA synthesis inhibitors, fibrosarcoma, p53-independent cell death
- MeSH terms
- Animals, Antineoplastic Agents, Cell Line, Transformed, DNA Repair, Enzyme Inhibitors, Etoposide, Iron Chelating Agents, Male, Mice, Nude, Neoplasms, Experimental, Transcription Factors, Tumor Suppressor Protein p53, Carboplatin, Apoptosis, Gene Deletion, Drug Resistance, Neoplasm, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Topoisomerase I Inhibitors
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