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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
Self-citationTalks, K. L., Turley, H., Gatter, K. C., Maxwell, P. H., Pugh, C. W., Ratcliffe, P. J., & Harris, A. L. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64554-3 · Cited by 1,312
Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response
Dewhirst, M. W., Cao, Y., & Moeller, B. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2397 · Cited by 1,022
Self-citationRadiation activates HIF-1 to regulate vascular radiosensitivity in tumors
Moeller, B. J., Cao, Y., Li, C. Y., & Dewhirst, M. W. (2004) · Cancer Cell · doi:10.1016/s1535-6108(04)00115-1 · Cited by 996
Self-citationRegulation and Destabilization of HIF-1α by ARD1-Mediated Acetylation
Jeong, J.-W., Bae, M.-K., Ahn, M.-Y., Kim, S.-H., Sohn, T.-K., Bae, M.-H., Yoo, M.-A., Song, E. J., Lee, K.-J., & Kim, K.-W. (2002) · Cell · doi:10.1016/s0092-8674(02)01085-1 · Cited by 716
HIF-1 as a target for drug development
Giaccia, A., Siim, B. G., & Johnson, R. S. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1199 · Cited by 631
Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant MCF-7 tumor
Lee, E. S., Na, K., & Bae, Y. H. (2005) · Journal of Controlled Release · doi:10.1016/j.jconrel.2004.12.018 · Cited by 577
The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors
Primeau, A. J., Rendon, A., Hedley, D., Lilge, L., & Tannock, I. F. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1664 · Cited by 499
Regulation of HIF-1α Stability through S-Nitrosylation
Li, F., Sonveaux, P., Rabbani, Z. N., Liu, S., Yan, B., Huang, Q., Vujašković, Ž., Dewhirst, M. W., & Li, C. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.02.024 · Cited by 444
Self-citationDetermination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors
Laginha, K. M., Verwoert, S., Charrois, G. J. R., & Allen, T. M. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-0343 · Cited by 441
Kimura, H., Weisz, A., Kurashima, Y., Hashimoto, K., Ogura, T., D’Acquisto, F., Addeo, R., Makuuchi, M., & Esumi, H. (2000) · Blood · doi:10.1182/blood.v95.1.189 · Cited by 437
Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells.
Fornari, F. A., Randolph, J. K., Yalowich, J. C., Ritke, M. K., & Gewirtz, D. A. (1994) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)10149-1 · Cited by 436
Nitric Oxide Impairs Normoxic Degradation of HIF-1α by Inhibition of Prolyl Hydroxylases
Metzen, E., Zhou, J., Jelkmann, W., Fandrey, J., & Brüne, B. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-12-0791 · Cited by 414
Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity
Moeller, B. J., Dreher, M. R., Rabbani, Z. N., Schroeder, T., Cao, Y., Li, C. Y., & Dewhirst, M. W. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.016 · Cited by 374
Self-citationCharrois, G. J. R., & Allen, T. M. (2004) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2004.03.006 · Cited by 304
Lee, T.-H., Seng, S., Sekine, M., Hinton, C. V., Fu, Y., Avraham, H. K., & Avraham, S. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040186 · Cited by 275
Accumulation of HIF-1α under the influence of nitric oxide
Sandau, K. B., Fandrey, J., & Brüne, B. (2001) · Blood · doi:10.1182/blood.v97.4.1009 · Cited by 263
Song, X., Liu, X., Chi, W., Liu, Y., Wei, L., Wang, X., & Yu, J. (2006) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-006-0224-7 · Cited by 262
Generali, D., Berruti, A., Brizzi, M. P., Campo, L., Bonardi, S., Wigfield, S., Bersiga, A., Allevi, G., Milani, M., Aguggini, S., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-2690 · Cited by 253
Pidgeon, G. P., Barr, M. P., Harmey, J. H., Foley, D. A., & Bouchier‐Hayes, D. J. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2001.1876 · Cited by 211
Nardinocchi, L., Puca, R., Sacchi, A., & D’Orazi, G. (2009) · Molecular Cancer · doi:10.1186/1476-4598-8-1 · Cited by 180
Moon, E. J., Sonveaux, P., Porporato, P. E., Danhier, P., Gallez, B., Batinic̈‐Haberle, I., Nien, Y.-C., Schroeder, T., & Dewhirst, M. W. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006646107 · Cited by 158
Self-citationBerchner‐Pfannschmidt, U., Yamac, H., Trinidad, B., & Fandrey, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m607065200 · Cited by 158
Gianni, L., Zweier, J. L., Levy, A., & Myers, C. E. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)88854-8 · Cited by 138
Adriamycin-stimulated hydroxyl radical formation in human breast tumor cells
Sinha, B. K., Katki, A. G., Batist, G., Cowan, K. H., & Myers, C. E. (1987) · Biochemical Pharmacology · doi:10.1016/0006-2952(87)90164-x · Cited by 109
Iwashina, M., Shichiri, M., Marumo, F., & Hirata, Y. (1998) · Circulation · doi:10.1161/01.cir.98.12.1212 · Cited by 102
Cao, Y., Sonveaux, P., Liu, S., Zhao, Y., Mi, J., Clary, B. M., Li, C., Kontos, C. D., & Dewhirst, M. W. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4056 · Cited by 101
Self-citationThomas, M., Finnegan, C. E., Rogers, K., Purcell, J. W., Trimble, A., Johnston, P. G., & Boland, M. P. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1864 · Cited by 100
Cao, Y., Li, C.-Y., Moeller, B. J., Yu, D., Zhao, Y., Dreher, M. R., Shan, S., & Dewhirst, M. W. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4553 · Cited by 92
Self-citationRelationship between radiation-induced G1 phase arrest and p53 function in human tumor cells.
Nagasawa, H., Li, C., Maki, C. G., Imrich, A., & Little, J. B. (1995) · PubMed · Cited by 84
Oxygen-sensing under the influence of nitric oxide
Berchner‐Pfannschmidt, U., Tug, S., Kirsch, M., & Fandrey, J. (2009) · Cellular Signalling · doi:10.1016/j.cellsig.2009.10.004 · Cited by 78
Guo, P., Fang, Q., Tao, H.-Q., Schafer, C. A., Fenton, B. M., Ding, I., Hu, B., & Cheng, S. (2003) · PubMed · Cited by 78
Menegazzi, M., Tedeschi, E., Dussin, D., de Prati, A. C., Cavalieri, E., Mariotto, S., & Suzuki, H. (2001) · The FASEB Journal · doi:10.1096/fj.00-0519fje · Cited by 73
Fryknäs, M., Dhar, S., Oberg, F. G., Rickardson, L., Rydåker, M., Göransson, H., Gustafsson, M. G., Pettersson, U., Nygren, P., Larsson, R. L., et al. (2006) · International Journal of Cancer · doi:10.1002/ijc.22291 · Cited by 65
Tsoyi, K., Nizamutdinova, I. T., Jang, H. J., Mun, L., Kim, H. J., Seo, H. G., Lee, J. H., & Chang, K. C. (2010) · Shock · doi:10.1097/shk.0b013e3181e46f15 · Cited by 63
Park, Y.-K., Ahn, D., Oh, M., Tae-Kyoung, L., Yang, E. G., Son, M., & Park, H. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.045278 · Cited by 52
Müerköster, S. S., Lust, J. A., Arlt, A., Häsler, R., Witt, M., Sebens, T., Schreiber, S., Fölsch, U. R., & Schäfer, H. (2006) · Oncogene · doi:10.1038/sj.onc.1209423 · Cited by 52
Photodynamic therapy mediates the oxygen-independent activation of hypoxia-inducible factor 1α
Mitra, S., Cassar, S. E., Niles, D. J., Puskas, J., Frelinger, J. G., & Foster, T. H. (2006) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0421 · Cited by 50
Wang, H., Mohammad, R. M., Werdell, J., & Shekhar, M. P. V. (1998) · International Journal of Molecular Medicine · doi:10.3892/ijmm.1.6.915 · Cited by 35
Yamaguchi, K., Saito, H., Oro, S., Tatebe, S., Ikeguchi, M., & Tsujitani, S. (2005) · Oncology · doi:10.1159/000086990 · Cited by 27
Li, L., Zhang, J., Jin, B., Block, E. R., & Patel, J. M. (2007) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-007-9529-z · Cited by 15
Cited by
Sorted by citations
Samanta, D., Gilkes, D. M., Chaturvedi, P., Xiang, L., & Semenza, G. L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1421438111 · Cited by 460
RetractedSemenza, G. L. (2016) · The EMBO Journal · doi:10.15252/embj.201695204 · Cited by 380
Lee, K., Kuo, Y., Ho, Y., & Huang, Y. (2019) · Cancers · doi:10.3390/cancers11091334 · Cited by 270
Mallini, P., Lennard, T. W. J., Kirby, J. A., & Meeson, A. P. (2013) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2013.09.008 · Cited by 247
Samanta, D., Park, Y., Andrabi, S. A., Shelton, L. M., Gilkes, D. M., & Semenza, G. L. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0530 · Cited by 242
Retracted
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
