The DOI matches its Crossref record; 50 of the 54 references it cites were found in a registry or an index.
Tumor Cells Upregulate Normoxic HIF-1α in Response to Doxorubicin
Open accessPublished version of a preprint
Abstract
Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that controls cellular homeostasis. Although its activation benefits normal tissue, HIF-1 activation in tumors is a major risk factor for angiogenesis, therapeutic resistance, and poor prognosis. HIF-1 activity is usually suppressed under normoxic conditions because of rapid oxygen-dependent degradation of HIF-1α. Here, we show that, under normoxic conditions, HIF-1α is upregulated in tumor cells in response to doxorubicin, a chemotherapeutic agent used to treat many cancers. In addition, doxorubicin enhanced VEGF secretion by normoxic tumor cells and stimulated tumor angiogenesis. Doxorubicin-induced accumulation of HIF-1α in normoxic cells was caused by increased expression and activation of STAT1, the activation of which stimulated expression of iNOS and its synthesis of nitric oxide (NO) in tumor cells. Mechanistic investigations established that blocking NO synthesis or STAT1 activation was sufficient to attenuate the HIF-1α accumulation induced by doxorubicin in normoxic cancer cells. To our knowledge, this is the first report that a chemotherapeutic drug can induce HIF-1α accumulation in normoxic cells, an efficacy-limiting activity. Our results argue that HIF-1α-targeting strategies may enhance doxorubicin efficacy. More generally, they suggest a broader perspective on the design of combination chemotherapy approaches with immediate clinical impact. Cancer Res; 73(20); 6230–42. ©2013 AACR.
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“In normoxic cancer cell lines, doxorubicin-induced HIF-1α accumulation was shown to depend on STAT1 activity, leading to increase in inducible nitric oxide synthase (iNOS) and nitric oxide production [396].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [396]
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“However, tumor cells can partially compensate for this inhibition by inducing HIF-1α expression.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [396]
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2 retracted
Zhang, H., Wong, C. C. L., Wei, H., Gilkes, D. M., Korangath, P., Chaturvedi, P., Schito, L., Chen, J., Krishnamachary, B., Winnard, P. T., et al. (2012) · Oncogene · doi:10.1038/onc.2011.365 · Cited by 326
RetractedLee, K., Qian, D. Z., Rey, S., Wei, H., Liu, J. O., & Semenza, G. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812801106 · Cited by 289
RetractedTargeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717 · cited 7×
“Hypoxia is one important factor for HIF-1 activation, VEGF expression and angiogenesis (1, 30, 39).”
InfluentialJaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735
Exploiting tumour hypoxia in cancer treatment
Brown, J. M., & Wilson, W. R. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1367 · Cited by 2,828
Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis
Carmeliet, P., Dor, Y., Herbert, J.-M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., et al. (1998) · Nature · doi:10.1038/28867 · Cited by 2,502
Hypoxia, HIF1 and glucose metabolism in the solid tumour
Denko, N. C. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2468 · Cited by 1,707
Lando, D., Peet, D. J., Gorman, J. J., Whelan, D. A., Whitelaw, M. L., & Bruick, R. K. (2002) · Genes & Development · doi:10.1101/gad.991402 · Cited by 1,550 · cited 2×
“Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor.”
Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells
Li, Z., Bao, S., Wu, Q., Wang, H., Eyler, C., Sathornsumetee, S., Shi, Q., Cao, Y., Lathia, J., McLendon, R. E., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.018 · Cited by 1,354
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Turdo, A., Todaro, M., & Stassi, G. (2015) · Springer eBooks · doi:10.1007/978-3-319-21030-8_16 · Cited by 1
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Yang, G., Ma, B., La, Y., Ma, X., Wu, X., Chu, M. K., Guo, X., Wang, L., & Liang, C. (2025) · Research Square · doi:10.21203/rs.3.rs-7466956/v1
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Impact of CaV1.3 L-Type Calcium Channels on Arrhythmogenesis in Cancer
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Prantner, D., Watson, M. A., Brand, M. D., Paton, J. C., & Vogel, S. N. (2026) · Immunometabolism · doi:10.1097/in9.0000000000000085
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Metadata
- Authors
- Cao, Y., Eble, J. M., Moon, E., Yuan, H., Weitzel, D. H., Landon, C. D., Yu-Chih Nien, C., Hanna, G., Rich, J. N., Provenzale, J. M., & Dewhirst, M. W.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Authors' Affiliations: Departments of 1Radiation Oncology,2Surgery, 3Pathology, and 4Radiology, Duke University Medical Center, Durham; 5Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 6Department of Radiology, Mayo Clinic, Rochester, Minnesota; 7Department of Radiation Oncology, Stanford University, Stanford, California; and 8Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
- Corresponding author
- Cao, Yiting
- Dewhirst, Mark W.
- Venue
- Cancer Research
- Published
- 2013-10-14
- Volume
- 73
- Issue
- 20
- Pages
- 6230-6242
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3800255
- OpenAlex
- W2143643269
- Cited by
- 111
- References
- 54
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 3 · 2023: 6 · 2022: 12 · 2021: 10 · 2020: 11 · 2019: 12 · 2018: 11 · 2017: 3 · 2016: 7 · 2015: 9 · 2014: 13 · 2013: 2
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p01ca042745-23)
- National Cancer Institute (P01-CA-42745, R01CA040355, R01 CA40355, P01-CA042745, P50CA068438, P30CA014236)
- 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 › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- HIF-1α, doxorubicin, normoxia, cancer cells, STAT1, inducible nitric oxide synthase, nitric oxide, vascular endothelial growth factor, tumor angiogenesis, chemoresistance, combination chemotherapy, HIF-1α stabilization
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Breast Neoplasms, Doxorubicin, Female, Humans, Mammary Neoplasms, Experimental, Mice, Nude, Nitric Oxide, Random Allocation, Transcription Factors, Up-Regulation, Cell Line, Tumor, STAT1 Transcription Factor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Nitric Oxide Synthase Type II, MCF-7 Cells
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