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Updated: Jan 13, 2026
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
The Olive Phenolic S-(-)-Hydroxyoleocanthal Attenuates Neuroendocrine Prostate Cancer via Modulation of
Md Towhidul Islam Tarun1, Hassan Y Ebrahim1,2, Khalid A El Sayed1
1School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA.
Abstract:
Background/Objectives. Prostate cancer (PCa) is the second leading cause of cancer-related mortality among men in the United States. Treatment with second-generation androgen receptor (AR) inhibitors, such as enzalutamide, can trigger lineage plasticity, promoting the transdifferentiation of PCa cells into an AR-independent, poorly differentiated neuroendocrine phenotype (NEPC). The receptor tyrosine kinase EPHA3 is a critical driver for NEPC. It is overexpressed in PCa, particularly in androgen-independent and neuroendocrine subtypes. EPHA3 activates c-Myc signaling to enhance EZH2 expression, promoting histone H3K27 trimethylation. The neural transcription factor BRN2 functions upstream of both EZH2 and ASCL1. The latter regulates the Notch pathway ligand DLL3, thereby orchestrating neuroendocrine differentiation. Elevated expression of classical neuroendocrine markers CHGA and SYP is characteristic of the NEPC phenotype. This study reports the novel usage of the olive phenolic S-(-)-hydroxyoleocanthal (HOC, oleacein) to effectively control NEPC by targeting the EPHA3-BRN2-EZH2-ASCL1-DLL3-SYP-CHGA oncogenic network. Methods. Cell viability assays were conducted to assess in vitro effects. To model NEPC progression and recurrence, NCI-H660-Luc cells were xenografted into male athymic nude mice. RNA-sequencing was performed to compare the differentially expressed genes between placebo control and treated tumors. Results. HOC significantly attenuated the proliferation of NEPC NCI-H660 cells in vitro. Daily oral administration of HOC at 10 mg/kg body weight markedly suppressed the progression of NEPC NCI-H660-Luc tumors. Continued HOC treatments after surgical excision of the primary tumors substantially reduced locoregional recurrence. HOC significantly downregulated the expression of EPHA3, BRN2, EZH2, ASCL1, DLL3, SYP, and CHGA in treated primary and recurrence tumors versus placebo control. Conclusions. These findings establish HOC as a multifaceted therapeutic entity capable of disrupting key NEPC oncogenic networks, highlighting its potential as a novel lead intervention for aggressive NEPC.
Insights
Olive phenolic S-(-)-hydroxyoleocanthal (HOC) effectively controls neuroendocrine prostate cancer (NEPC) by targeting key oncogenic networks. HOC suppresses NEPC progression and recurrence, offering a novel therapeutic potential for aggressive prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer (PCa) mortality is high, with lineage plasticity leading to aggressive neuroendocrine prostate cancer (NEPC) under treatment.
- EPHA3 receptor tyrosine kinase drives NEPC by activating the EPHA3-BRN2-EZH2-ASCL1-DLL3-SYP-CHGA oncogenic network.
- Current treatments can induce NEPC, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of S-(-)-hydroxyoleocanthal (HOC), an olive phenolic compound, in controlling NEPC.
- To determine HOC's ability to target the EPHA3-driven oncogenic network in NEPC.
- To evaluate HOC's potential as a novel therapeutic intervention for aggressive NEPC.
Main Methods:
- In vitro cell viability assays using NEPC NCI-H660 cells.
- In vivo xenograft mouse model using NCI-H660-Luc cells to assess NEPC progression and recurrence.
- RNA-sequencing analysis to compare gene expression profiles between HOC-treated and placebo groups.
Main Results:
- HOC significantly inhibited NEPC cell proliferation in vitro.
- Oral administration of HOC suppressed NEPC tumor progression and reduced locoregional recurrence post-surgery in vivo.
- HOC treatment markedly downregulated key oncogenic markers including EPHA3, BRN2, EZH2, ASCL1, DLL3, SYP, and CHGA.
Conclusions:
- S-(-)-hydroxyoleocanthal (HOC) demonstrates significant therapeutic potential against NEPC.
- HOC effectively disrupts the critical EPHA3-BRN2-EZH2-ASCL1-DLL3-SYP-CHGA oncogenic network driving NEPC.
- HOC represents a promising novel lead intervention for aggressive NEPC.
