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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.
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“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]
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Reyes‐Castellanos, G. (2021) · theses.fr (ABES) · doi:10.70675/461953f3z886ez4342za1e2z84c44a9fcaa6
Cheng, S.-H., Peng, R., Wu, C., Luo, C., Raj, E. N., Wen, Z., Hsiao, T., & Liu, W. (2026) · Advanced Science · doi:10.1002/advs.77941
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
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