ArticleOncogene2018
Metformin sensitizes endometrial cancer cells to chemotherapy through IDH1-induced Nrf2 expression via an epigenetic mechanism.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
38 citing papers in PubMed, 79 citations in OpenAlex.
- Reprogramming oncogenic mitochondria in pancreatic adenocarcinoma through BRD4 inhibition leads to programmed cell death.The Journal of pharmacology and experimental therapeutics · 2025Article
- The role of NRF2 function and regulation in atherosclerosis: an update.Molecular and cellular biochemistry · 2025Review
- Metformin in gynecological disorders: pathogenic insights and therapeutic implications.Frontiers in pharmacology · 2025Review
- Metformin Regulates Cardiac Ferroptosis to Reduce Metabolic Syndrome-Induced Cardiac Dysfunction.Applied biochemistry and biotechnology · 2025Article
- The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity.Antioxidants (Basel, Switzerland) · 2024Review
- Phosphorylation of IDH1 Facilitates Progestin Resistance in Endometrial Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Metformin alleviates adriamycin resistance of osteosarcoma by declining YY1 to inhibit MDR1 transcriptional activity.BMC pharmacology & toxicology · 2023Article
- Redox Regulation of Nrf2 in Cisplatin-Induced Kidney Injury.Antioxidants (Basel, Switzerland) · 2023Review
- How to deal with frenemy NRF2: Targeting NRF2 for chemoprevention and cancer therapy.Journal of food and drug analysis · 2023Review
- Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity.Journal of pharmaceutical analysis · 2023Article
- Metformin induces autophagy of cisplatin-resistant human gastric cancer cells in addition to apoptosis.BioMedicine · 2023Article
- NrCAM secreted by endometrial stromal cells enhances the progestin sensitivity of endometrial cancer cells through epigenetic modulation of PRB.Cancer gene therapy · 2022Article
- A Comprehensive Review on Beneficial Effects of Catechins on Secondary Mitochondrial Diseases.International journal of molecular sciences · 2022Review
- Article
- Metformin and Cancer, an Ambiguanidous Relationship.Pharmaceuticals (Basel, Switzerland) · 2022Review
- A Clinical Perspective of the Multifaceted Mechanism of Metformin in Diabetes, Infections, Cognitive Dysfunction, and Cancer.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma.Acta pharmaceutica Sinica. B · 2022Review
- Ferroptosis: Opportunities and Challenges in Treating Endometrial Cancer.Frontiers in molecular biosciences · 2022Review
- Dipeptidyl Peptidase (DPP)-4 Inhibitor Impairs the Outcomes of Patients with Type 2 Diabetes Mellitus After Curative Resection for Colorectal Cancer.Cancer research communications · 2021Article
- New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 2 countries.
Funding
Abstract
Chemoresistance is the major obstacle to cure endometrial cancer, whereas metformin has demonstrated sensitization to chemotherapy in endometrial cancer. A novel finding states that isocitrate dehydrogenase 1 (IDH1) involves in cancer chemoresistance. Recent studies have revealed that epigenetic modifications facilitate chemoresistance. However, whether IDH1 play a role in metformin-induced endometrial cancer chemosensitivity through epigenetic modification is incompletely understood. Immunohistochemistry and Elisa assays were used to evaluate the expression pattern of IDH1 in endometrial tissue and serum, respectively. Western blot was performed to determine changes in expression of key molecules in the IDH1-ɑ-KG-TET1-Nrf2 signaling pathway after various treatments. Dot blot assays were used to assess global hydroxymethylation levels after metformin administration or plasmid transfection. Antioxidant response element (ARE) activity in the IDH1 promoter region was monitored by luciferase assay. Cancer cell sensitivity to chemotherapy was detected by SRB assay. We found that activation of the IDH1 signaling pathway in endometrial cancer tissue resulting from aberrant expression of IDH1 and its downstream mediators conferred chemoresistance. We found that this effect was abated by metformin treatment. Dot blot and HMeDIP assays revealed that metformin blocked IDH1-ɑ-KG-TET1-mediated enhancement of Nrf2 hydroxymethylation levels, eliminating chemoresistance. Moreover, we observed that chemoresistance was enhanced via a regulatory loop in which Nrf2 activated IDH1-ɑ-KG-TET1-Nrf2 signaling via binding to the ARE sites in the IDH1 promoter region. Our findings highlight a critical role of IDH1-ɑ-KG-TET1-Nrf2 signaling in chemoresistance and suggest that rational combination therapy with metformin and chemotherapeutics has the potential to suppress chemoresistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.