ArticleAmerican journal of translational research2024
NOTCH1 regulates the DNA damage response and sorafenib resistance by activating ATM in hepatocellular carcinoma.
Article in American journal of translational research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- MYC-SNHG7-miR-34a-5p Feedback Loop Orchestrates GSDMD-Dependent Pyroptosis in Hepatocellular Carcinoma.International journal of molecular sciences · 2026Article
- AKT, ATR, and Notch Inhibitors Radiosensitize a Preclinical Model of Adenoid Cystic Carcinoma.Head & neck · 2026Article
- CRISPR-Cas9 screening identifies ATOX1-driven cisplatin resistance mechanisms in liver cancer and evaluates targeted inhibitor efficacy.Communications biology · 2026Article
- Post-translational modification in hepatocellular carcinoma resistance: molecular mechanisms and therapeutic targeting.Frontiers in immunology · 2026Review
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Authors and funding
7 authors.
Funding
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Abstract
objectiveThis study investigates the mechanism underlying sorafenib resistance in hepatocellular carcinoma cells (HCC), focusing on DNA damage repair (DDR) pathways to develop targeted therapeutic strategies.
methodsBioinformatics analysis was used to screen genes associated with sorafenib resistance, which was further demonstrated by western blotting. Cell proliferation was determined using the EdU assay. The presence of binding sites between valproic acid (VPA) and NOTCH1 was analyzed by molecular docking. Comet and flow cytometry assays evaluated DNA damage and cell cycle arrest induced by VPA in sorafenib-resistant cells, with further mechanistic insights gained via western blotting and co-immunoprecipitation (Co-IP).
resultsWe found that NOTCH1/ATM axis plays a vital role in the prognosis of patients with liver cancer and in the behavior of sorafenib-resistant cells. HCC resistant to sorafenib exhibited enhanced cell proliferation ability. Moreover, overexpression of NOTCH1 in sorafenib-sensitive HCC cells significantly increased liver cancer cell proliferation. Conversely, silencing NOTCH1 expression in sorafenib-resistant HCC cell lines reduced their proliferative activity. Additionally, VPA enhanced the therapeutic efficacy against sorafenib-resistance cells by modulating NOTCH1/ATM/p-BRCA1/p-CHK2/γ-H2AX signaling axis and homologous recombination (HR) activity.
conclusionTargeting NOTCH1 and ATM is a promising strategy to overcome sorafenib resistance in HCC, particularly through the combined use of VPA and sorafenib.
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