ArticleDiscover oncology2024
Pralatrexate represses the resistance of HCC cells to molecular targeted agents via the miRNA-34a/Notch pathway.
Article in Discover oncology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Pralatrexate is a potent pan-serotype human adenovirus inhibitor through suppression of dihydrofolate reductase.Antimicrobial agents and chemotherapy · 2026Article
- Let-7a and miR-34a Interplay Potent Suppressive Roles in Hepatocellular Carcinoma via Co-TargetingInternational journal of molecular sciences · 2026Article
- Bridging mechanism and design: modern medicinal chemistry approaches to thymidylate synthase inhibitors.RSC advances · 2026Review
- Notch signaling in liver diseases: mechanistic insights and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- PRMT1-catalyzed NUSAP1 methylation enhances Notch2 signaling and 5-FU resistance in gastric cancer.Cell death & disease · 2025Article
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Authors and funding
8 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Metabolism-related pathways are important targets for intervention in the treatment of hepatocellular carcinoma (HCC), but few studies have reported on the combination of inhibitors of folate metabolism-related enzymes and molecularly targeted drugs for HCC. The results of the present work are the first to reveal the effects of an inhibitor of dihydrofolate reductase (DHFR), pralatrexate, on the sensitivity of HCC cells to molecularly targeted agents examined using multiple assays. In HCC cells, knockdown of DHFR or treatment with pralatrexate enhanced the sensitivity of HCC cells to molecularly targeted agents, such as sorafenib, regorafenib, lenvatinib, cabozantinib, or anlotinib. Mechanically, pralatrexate decreased the methylation rates of miRNA-34a's promoter region to enhance the expression of miRNA-34a. Treatment with pralatrexate inhibited the expression of Notch and its downstream factors by enhancing the expression of miRNA-34a in HCC cells. In clinical specimens, the expression of miRNA-34a was negatively correlated with DHFR expression, while DHFR expression was positively correlated with the Notch intracellular domain (NICD) and downstream factors of the Notch pathway. The expression of miRNA-34a was negatively correlated with DHFR expression, while the methylation rates of miRNA-34a's promoter were positively related to DHFR. The effect of pralatrexate on the metabolic profile of HCC cells is very different from that of small molecule inhibitors related to glycolipid metabolism. Therefore, pralatrexate upregulates the sensitivity of HCC cells to molecularly targeted drugs. These results expand our understanding of folate metabolism and HCC and can help provide more options for HCC treatment.
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