Related Experiment Video

Updated: Jun 1, 2025

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
09:08

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer

Published on: January 12, 2020

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NOTCH1 regulates the DNA damage response and sorafenib resistance by activating ATM in hepatocellular carcinoma

Jing Liu1, Yan Yu1, Bin Xu2

  • 1Department of Pharmacy, Shanghai Fifth People's Hospital, Fudan University 801 Heqing Road, Shanghai 200240, China.

American Journal of Translational Research
|January 17, 2025
PubMed
Abstract

Insights

Targeting the NOTCH1/ATM pathway with valproic acid (VPA) can overcome sorafenib resistance in hepatocellular carcinoma (HCC). This approach modulates DNA damage repair, offering a new therapeutic strategy for liver cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Hepatocellular carcinoma (HCC) frequently develops resistance to sorafenib, a standard treatment.
  • Understanding the molecular mechanisms of sorafenib resistance is crucial for developing effective therapies.
  • DNA damage repair (DDR) pathways are implicated in cancer drug resistance.

Purpose of the Study:

  • To investigate the role of DNA damage repair (DDR) pathways in sorafenib resistance in HCC.
  • To identify potential therapeutic targets to overcome sorafenib resistance.
  • To evaluate the efficacy of valproic acid (VPA) in combination with sorafenib.

Main Methods:

  • Bioinformatics analysis and western blotting to identify key genes.
  • EdU assay for cell proliferation assessment.
  • Molecular docking, comet assay, flow cytometry, western blotting, and co-immunoprecipitation to elucidate mechanisms.

Main Results:

  • The NOTCH1/ATM axis was identified as critical in sorafenib resistance and HCC prognosis.
  • NOTCH1 overexpression enhanced HCC cell proliferation, while its silencing reduced it.
  • VPA treatment modulated the NOTCH1/ATM/p-BRCA1/p-CHK2/γ-H2AX signaling axis and homologous recombination (HR) activity, enhancing therapeutic efficacy.

Conclusions:

  • Targeting NOTCH1 and ATM presents a promising strategy to combat sorafenib resistance in HCC.
  • Combined therapy with VPA and sorafenib demonstrates potential for overcoming resistance and improving treatment outcomes.
Keywords:
ATMNOTCH1RAD51sorafenib resistancevalproic acid

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