Tumor Cells Upregulate Normoxic HIF-1α in Response to Doxorubicin

Cao, Yiting; Eble, Joseph M.; Moon, Ejung; Yuan, Hong; Weitzel, Douglas H.; Landon, Chelsea D.; Yu-Chih Nien, Charleen; Hanna, Gabi; Rich, Jeremy N.; Provenzale, James M.; Dewhirst, Mark W.

doi:10.1158/0008-5472.can-12-1345

Cited by 111Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerCancer, Lipids, and Metabolism

Tumor Cells Upregulate Normoxic HIF-1α in Response to Doxorubicin

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Cao, Yiting, Eble, Joseph M., Moon, Ejung, Yuan, Hong, Weitzel, Douglas H., Landon, Chelsea D., Yu-Chih Nien, Charleen, Hanna, Gabi +3 more·2013·Cancer Research

DOI 10.1158/0008-5472.can-12-1345PMC PMC3800255

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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 depends on STAT1 activity, leading to increase in iNOS and nitric oxide production.
“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]
Tumor cells can partially compensate for anthracycline inhibition by inducing HIF-1α expression.
“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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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.
ORCID: Cao, Yiting
Eble, Joseph M.
Yuan, Hong
Landon, Chelsea D.
Rich, Jeremy N.
Dewhirst, Mark W.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2013-10-14
Volume: 73
Issue: 20
Pages: 6230-6242
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-12-1345
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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Tumor Cells Upregulate Normoxic HIF-1α in Response to Doxorubicin

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