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Updated: Jun 25, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Exploring the molecular link between arecoline exposure and prostate cancer-related alterations: integrative evidence
Xinyao Zhu1,2, Haixia Liu1,2, Zhiqiang Zeng1
1Department of Urology, Santai Hospital Affiliated to North Sichuan Medical College, Mianyang, Sichuan, China.
Abstract:
Arecoline, the major alkaloid of areca nut, is a common exposure in chewing products, but its relationship with prostate cancer (PCa) is unclear. We integrated network toxicology, bulk RNA machine learning, single-cell transcriptomics, molecular simulation, and in vitro validation to prioritize candidate molecular nodes potentially linking arecoline exposure to PCa-related alterations. Potential arecoline targets were intersected with PCa-related genes, followed by protein-protein interaction and enrichment analyses. Candidate genes were prioritized using TCGA-PRAD and external GEO cohorts, then refined in GWAS-relevant epithelial subpopulations from GSE141445. AR was further evaluated by the Human Protein Atlas, molecular docking, molecular dynamics, RT-qPCR, and Western blotting. We identified 97 overlapping targets enriched mainly in apoptosis-, p53-, and MAPK-related pathways. The optimal bulk RNA model showed good external performance (AUC = 0.956). Integrative analyses identified androgen receptor (AR) as the only consensus core gene. AR-high epithelial cells showed increased androgen response, mTORC1 signaling, and MYC targets. Molecular simulation provided computational support for structural compatibility between arecoline and AR, while in vitro experiments showed increased AR mRNA and protein expression after arecoline treatment in LNCaP cells. These findings suggest AR as a plausible candidate molecular node linking arecoline exposure to PCa-related molecular alterations and provide a hypothesis-generating framework for future mechanistic and exposure-focused studies.
Insights
Arecoline exposure may link to prostate cancer (PCa) through the androgen receptor (AR). This study identified AR as a key molecular node, with arecoline potentially increasing AR expression in PCa cells.
Area of Science:
- Oncology
- Toxicology
- Bioinformatics
Background:
- Arecoline, found in areca nut products, is widely consumed but its role in prostate cancer (PCa) development is not well understood.
- Understanding molecular links between arecoline exposure and PCa is crucial for public health and targeted interventions.
Purpose of the Study:
- To investigate the molecular mechanisms connecting arecoline exposure to prostate cancer (PCa).
- To identify key molecular targets and pathways involved in arecoline-induced PCa alterations using an integrated approach.
Main Methods:
- Integrated network toxicology, machine learning on bulk RNA sequencing, single-cell transcriptomics, molecular simulation, and in vitro validation.
- Prioritized candidate genes by intersecting arecoline targets with PCa-related genes, followed by pathway and protein-protein interaction analyses.
- Validated the role of the androgen receptor (AR) through molecular docking, dynamics, RT-qPCR, and Western blotting.
Main Results:
- Identified 97 overlapping targets enriched in apoptosis, p53, and MAPK pathways.
- Developed a predictive bulk RNA model for PCa with high external validation (AUC = 0.956).
- Consensus core gene analysis pinpointed the androgen receptor (AR) as the primary molecular link, with arecoline increasing AR expression and related signaling in prostate cancer cells.
Conclusions:
- Androgen receptor (AR) is a plausible molecular node connecting arecoline exposure to prostate cancer (PCa) pathogenesis.
- Findings provide a framework for future mechanistic studies on arecoline's role in PCa and highlight AR as a potential therapeutic target.
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