ArticleCell death & disease2021
Metformin sensitises hepatocarcinoma cells to methotrexate by targeting dihydrofolate reductase.
Article in Cell death & disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 15 citations in OpenAlex.
- Investigating the interaction between aryl hydrocarbon receptor and methotrexate: implications for treatment resistance in rheumatoid arthritis patients.Pharmacological reports : PR · 2026Article
- Protodioscin enhances Methotrexate-induced senescence and senolytic activity in HepG2 liver cancer spheroids by modulating cell cycle regulators and the TGF-β/p-Smad2-4 signaling pathway.Scientific reports · 2025Article
- Combating Methotrexate Resistance in Cancer Treatment: A Review on Navigating Pathways and Enhancing Its Efficacy With Fat-Soluble Vitamins.Scientifica · 2025Review
- Tumor organoids for primary liver cancers: A systematic review of current applications in diagnostics, disease modeling, and drug screening.JHEP reports : innovation in hepatology · 2024Article
- Three-Dimensional Hepatocyte Spheroids: Model for Assessing Chemotherapy in Hepatocellular Carcinoma.Biomedicines · 2024Article
- Metformin: A Dual-Role Player in Cancer Treatment and Prevention.International journal of molecular sciences · 2024Review
- Identification of glucose-independent and reversible metabolic pathways associated with anti-proliferative effect of metformin in liver cancer cells.Metabolomics : Official journal of the Metabolomic Society · 2024Article
- The development and benefits of metformin in various diseases.Frontiers of medicine · 2023Review
- Liver organoids: a promising three-dimensional model for insights and innovations in tumor progression and precision medicine of liver cancer.Frontiers in immunology · 2023Review
- A statistical framework for high-content phenotypic profiling using cellular feature distributions.Communications biology · 2022Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
Metformin, the first-line drug for type II diabetes, has recently been considered an anticancer agent. However, the molecular target and underlying mechanism of metformin's anti-cancer effects remain largely unclear. Herein, we report that metformin treatment increases the sensitivity of hepatocarcinoma cells to methotrexate (MTX) by suppressing the expression of the one-carbon metabolism enzyme DHFR. We show that the combination of metformin and MTX blocks nucleotide metabolism and thus effectively inhibits cell cycle progression and tumorigenesis. Mechanistically, metformin not only transcriptionally represses DHFR via E2F4 but also promotes lysosomal degradation of the DHFR protein. Notably, metformin dramatically increases the response of patient-derived hepatocarcinoma organoids to MTX without obvious toxicity to organoids derived from normal liver tissue. Taken together, our findings identify an important role for DHFR in the suppressive effects of metformin on therapeutic resistance, thus revealing a therapeutically targetable potential vulnerability in hepatocarcinoma.
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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.