The DOI matches its Crossref record; 40 of the 41 references it cites were found in a registry or an index.
High Levels of Nrf2 Determine Chemoresistance in Type II Endometrial Cancer
Open accessAbstract
Type II endometrial cancer, which mainly presents as serous and clear cell types, has proved to be the most malignant and recurrent carcinoma among various female genital malignancies. The transcription factor Nrf2 was first described as having chemopreventive activity. Activation of the Nrf2-mediated cellular defense response protects cells against the toxic and carcinogenic effects of environmental insults by upregulating an array of genes that detoxify reactive oxygen species and restore cellular redox homeostasis. However, the cancer-promoting role of Nrf2 has recently been revealed. Nrf2 is constitutively upregulated in several types of human cancer tissues and cancer cell lines. Furthermore, inhibition of Nrf2 expression sensitizes cancer cells to chemotherapeutic drugs. In this study, the constitutive level of Nrf2 was compared in different types of human endometrial tumors. It was found that Nrf2 was highly expressed in endometrial serous carcinoma (ESC), whereas complex hyperplasia and endometrial endometrioid carcinoma (EEC) had no or marginal expression of Nrf2. Likewise, the ESC-derived SPEC-2 cell line had a higher level of Nrf2 expression and was more resistant to the toxic effects of cisplatin and paclitaxel than the Ishikawa cell line, which was generated from EEC. Silencing of Nrf2 rendered SPEC-2 cells more susceptible to chemotherapeutic drugs, whereas it had a limited effect on Ishikawa cells. Inhibition of Nrf2 expression by overexpressing Keap1 sensitized SPEC-2 cells or SPEC-2-derived xenografts to chemotherapeutic treatments using both cell culture and severe combined immunodeficient mouse models. Collectively, we provide a molecular basis for the use of Nrf2 inhibitors to increase the efficacy of chemotherapeutic drugs and to combat chemoresistance, the biggest obstacle in chemotherapy.
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?
In the citing paper
“The resultant upregulation of Nrf2-mediated antioxidant proteins renders cancer cells resistant to chemotherapeutic drugs (e.g., cisplatin, 5-fluorouracil, docetaxel, and bortezomib) and radiotherapy [47,161,165,178,179,180,181,182,183,184].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [182]
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
Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., & Thun, M. J. (2009) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.20006 · Cited by 9,709
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630
Cancer chemoprevention with dietary phytochemicals
Surh, Y.-J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1189 · Cited by 2,955
Two pathogenetic types of endometrial carcinoma
Bokhman, J. V. (1983) · Gynecologic Oncology · doi:10.1016/0090-8258(83)90111-7 · Cited by 2,508
Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224
Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex
Zhang, D. D., Lo, S., Cross, J. V., Templeton, D. J., & Hannink, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.24.10941-10953.2004 · Cited by 1,284
Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway
Zhang, D. D. (2006) · Drug Metabolism Reviews · doi:10.1080/03602530600971974 · Cited by 1,105
Ramos-Gomez, M., Kwak, M.-K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P., & Kensler, T. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051618798 · Cited by 1,102
Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., et al. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030420 · Cited by 1,060
Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice
Rangasamy, T., Cho, C. Y., Thimmulappa, R. K., Zhen, L., Srisuma, S., Kensler, T. W., Yamamoto, M. P., Petrache, I., Tuder, R. M., & Biswal, S. S. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21146 · Cited by 993
NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer
Hayes, J. D., & McMahon, M. J. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2008.12.008 · Cited by 870
Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2
Wang, X.-J., Sun, Z., Villeneuve, N. F., Zhang, S., Zhao, F., Li, Y., Chen, W., Yi, X., Zheng, W., Wondrak, G. T., et al. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn095 · Cited by 839
Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
Padmanabhan, B., Tong, K. I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.-I., Kobayashi, A., Yokoyama, S., & Yamamoto, M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.013 · Cited by 735
Role of NRF2 in Protection Against Hyperoxic Lung Injury in Mice
Cho, H., Jedlicka, A., Reddy, S. P., Kensler, T. W., Yamamoto, M. P., Zhang, L.-Y., & Kleeberger, S. R. (2002) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.26.2.4501 · Cited by 660
LAU, A., VILLENEUVE, N., Sun, Z., Wong, P. K., & Zhang, D. (2008) · Pharmacological Research · doi:10.1016/j.phrs.2008.09.003 · Cited by 653
Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response
Chen, W., Sun, Z., Wang, X.-J., Jiang, T., Huang, Z., Fang, D., & Zhang, D. D. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.04.029 · Cited by 638
Self-citationDisruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice
Rangasamy, T., Guo, J., Mitzner, W. A., Roman, J., Singh, A., Fryer, A. D., Yamamoto, M., Kensler, T. W., Tuder, R. M., Georas, S. N., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050538 · Cited by 580
Molecular and Pathologic Aspects of Endometrial Carcinogenesis
Hecht, J. L., & Mutter, G. L. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.06.7173 · Cited by 536
Theories of Endometrial Carcinogenesis: A Multidisciplinary Approach
Sherman, M. E. (2000) · Modern Pathology · doi:10.1038/modpathol.3880051 · Cited by 511
The Protective Role of Nrf2 in Streptozotocin-Induced Diabetic Nephropathy
Jiang, T., Huang, Z., Lin, Y., Zhang, Z., Fang, D., & Zhang, D. D. (2010) · Diabetes · doi:10.2337/db09-1342 · Cited by 440
Singh, A., Boldin‐Adamsky, S., Thimmulappa, R. K., Rath, S. K., Ashush, H., Coulter, J. B., Blackford, A. L., Goodman, S. N., Bunz, F., Watson, W. H., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1401 · Cited by 371
Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin
Kim, Y. R., Oh, J. E., Kim, M. S., Kang, M. R., Park, S. W., Han, J. Y., Eom, H., Yoo, N. J., & Lee, S. H. (2009) · The Journal of Pathology · doi:10.1002/path.2653 · Cited by 357
Kensler, T. W., Chen, J., Egner, P. A., Fahey, J. W., Jacobson, L. P., Stephenson, K. K., Ye, L., Coady, J. L., Wang, J.-B., Wu, Y., et al. (2005) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-05-0368 · Cited by 317
MacLeod, A. K., McMahon, M. J., Plummer, S. M., Higgins, L. G., Penning, T. M., Igarashi, K., & Hayes, J. D. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp176 · Cited by 305
Yates, M. S., Tauchi, M., Katsuoka, F., Flanders, K. C., Liby, K. T., Honda, T., Gribble, G. W., Johnson, D. A., Johnson, J. A., Burton, N. C., et al. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0516 · Cited by 292
Shin, S., Wakabayashi, J., Yates, M. S., Wakabayashi, N., Dolan, P. M., Aja, S. M., Liby, K. T., Sporn, M. B., Yamamoto, M. P., & Kensler, T. W. (2009) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2009.08.022 · Cited by 275
A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity
Nioi, P., & Nguyen, T. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.08.051 · Cited by 212
Nrf2 as a target for cancer chemoprevention
Yu, X. Y., & Kensler, T. W. (2005) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2005.04.017 · Cited by 199
In vivo modulation of the Parkinsonian phenotype by Nrf2
Burton, N. C., Kensler, T. W., & Guilarte, T. R. (2006) · NeuroToxicology · doi:10.1016/j.neuro.2006.07.019 · Cited by 187
Higgins, L. G., Kelleher, M., Eggleston, I. M., Itoh, K., Yamamoto, M. P., & Hayes, J. D. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.03.005 · Cited by 178
Cho, J., Manandhar, S., Lee, H., Park, H.-M., & Kwak, M. (2007) · Cancer Letters · doi:10.1016/j.canlet.2007.10.022 · Cited by 167
Resistance to chemotherapy and hormone therapy in endometrial cancer
Chaudhry, P., & Asselin, É. (2009) · Endocrine Related Cancer · doi:10.1677/erc-08-0266 · Cited by 137
Shim, G.-S., Manandhar, S., Shin, D., Kim, T., & Kwak, M. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.09.006 · Cited by 131
Nrf2 protects against As(III)-induced damage in mouse liver and bladder
Jiang, T., Huang, Z., Chan, J. Y., & Zhang, D. D. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.06.010 · Cited by 92
Prognostic factors in endometrial carcinoma
Uharček, P. (2008) · Journal of obstetrics and gynaecology research · doi:10.1111/j.1447-0756.2008.00796.x · Cited by 89
Dietary Cancer Chemopreventive Agents – Targeting Inflammation and Nrf2 Signaling Pathway
Khor, T. O., Yu, S., & Kong, A. T. (2008) · Planta Medica · doi:10.1055/s-0028-1088303 · Cited by 64
Nordström, B., Strang, P. M., Lindgren, A., Bergström, R., & Tribukait, B. (1996) · PubMed · Cited by 36
Clinical aspects of uterine papillary serous carcinoma
Hamilton, C. A., Kapp, D. S., & Chan, J. K. (2008) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/gco.0b013e3282f2b10d · Cited by 28
Boyd, J. A., Rinehart, C. A., Walton, L. A., Siegal, G. P., & Kaufman, D. G. (1990) · In Vitro Cellular & Developmental Biology - Plant · doi:10.1007/bf02624426 · Cited by 25
Cited by
Sorted by citations
Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy
Forman, H. J., & Zhang, H. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00233-1 · Cited by 2,900
Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution
Taguchi, K., Motohashi, H., & Yamamoto, M. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2010.01473.x · Cited by 1,478
Ferroptosis: Mechanisms and links with diseases
Yan, H.-F., Zou, T., Tuo, Q.-Z., Xu, S., Li, H., Belaidi, A. A., & Lei, P. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00428-9 · Cited by 1,471
The emerging role of the Nrf2–Keap1 signaling pathway in cancerPreprint
Jaramillo, M. C., & Zhang, D. D. (2013) · Genes & Development · doi:10.1101/gad.225680.113 · Cited by 1,326
Role of Glutathione in Cancer Progression and Chemoresistance
Traverso, N., Ricciarelli, R., Nitti, M., Marengo, B., Furfaro, A. L., Pronzato, M. A., Marinari, U. M., & Domenicotti, C. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/972913 · Cited by 1,208
Metadata
- Authors
- Jiang, T., Chen, N., Zhao, F., Wang, X.-J., Kong, B., Zheng, W., & Zhang, D. D.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Zheng, Wenxin
- Zhang, Donna D.
- Venue
- Cancer Research
- Published
- 2010-06-30
- Volume
- 70
- Issue
- 13
- Pages
- 5486-5496
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2896449
- OpenAlex
- W2165167356
- Cited by
- 286
- References
- 41
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 9 · 2023: 17 · 2022: 19 · 2021: 20 · 2020: 14 · 2019: 21 · 2018: 13 · 2017: 24 · 2016: 25 · 2015: 27 · 2014: 18 · 2013: 19 · 2012: 26
- FWCI
- 8.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30 CA 23074, P30CA023074)
- National Institute of Environmental Health Sciences (R01ES015010, (ES015010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- Nrf2, type II endometrial cancer, chemoresistance, serous endometrial carcinoma, endometrioid endometrial cancer, complex hyperplasia, cisplatin resistance, paclitaxel resistance, Keap1, Nrf2 inhibitors, xenografts, redox homeostasis, detoxification genes
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Aged, Aged, 80 and over, Animals, Cisplatin, Female, Humans, Middle Aged, RNA, Messenger, Transfection, Mice, SCID, Endometrial Neoplasms, Apoptosis, Paclitaxel, Carcinoma, Endometrioid, Cystadenocarcinoma, Serous, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, RNA, Small Interfering, Intracellular Signaling Peptides and Proteins, Cell Growth Processes, NF-E2-Related Factor 2, Mice, Gene Knockdown Techniques
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
