Penfluridol suppresses MYC-driven ANLN expression and liver cancer progression by disrupting the KEAP1-NRF2 interaction
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View abstract on PubMed
Summary
This summary is machine-generated.The antipsychotic drug penfluridol effectively suppresses anillin (ANLN) in liver cancer cells by targeting the MYC/NRF2/KEAP1 pathway. This novel ANLN blocker shows potential for treating hepatocellular carcinoma (HCC).
Area Of Science
- Oncology
- Molecular Biology
- Pharmacology
Background
- Hepatocellular carcinoma (HCC) has a poor prognosis, especially in advanced stages.
- Anillin (ANLN) is crucial for cell growth and cytokinesis, and its overexpression is linked to HCC development and poor patient survival.
- Currently, no drugs are known to inhibit ANLN.
Purpose Of The Study
- To identify potential therapeutic agents that suppress ANLN expression in HCC.
- To elucidate the mechanism by which penfluridol affects ANLN expression and HCC progression.
- To evaluate the efficacy of penfluridol in preclinical HCC models.
Main Methods
- Analysis of The Cancer Genome Atlas (TCGA) data for ANLN expression and patient prognosis.
- Screening the Connectivity Map database to identify compounds affecting ANLN.
- In vitro studies involving liver cancer cell lines to assess ANLN knockdown effects and penfluridol's impact on proliferation, cell cycle, and colony formation.
- Investigating the molecular mechanism involving MYC, NRF2, and KEAP1.
- In vivo studies using a syngeneic mouse model of liver cancer.
Main Results
- High ANLN expression correlates with poor prognosis in HCC patients.
- Penfluridol significantly downregulates ANLN at both mRNA and protein levels, inducing G2/M cell cycle arrest and reducing colony formation.
- Penfluridol inhibits MYC binding to the ANLN promoter by upregulating NRF2, which sequesters MYC.
- Penfluridol enhances NRF2 activity by disrupting the NRF2-KEAP1 interaction.
- In vivo, penfluridol suppressed tumor growth, increased NRF2, and decreased MYC and ANLN levels.
Conclusions
- Penfluridol is the first identified ANLN suppressor with potential therapeutic application in HCC.
- Penfluridol modulates the MYC/NRF2/KEAP1 axis, offering a novel therapeutic strategy for liver cancer.
- Targeting ANLN represents a promising approach for improving HCC treatment outcomes.
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