# The Olive Phenolic S-(-)-Hydroxyoleocanthal Attenuates Neuroendocrine Prostate Cancer via Modulation of EPHA3-Centered Oncogenic Network

## TL;DR

A compound from olive oil, HOC, shows promise in treating aggressive prostate cancer by targeting key cancer-driving pathways.

## Contribution

HOC is shown to disrupt the EPHA3-centered oncogenic network in neuroendocrine prostate cancer.

## Key findings

- HOC significantly reduced the expression of EPHA3, BRN2, and downstream effectors in NEPC tumors.
- HOC treatment suppressed tumor progression and reduced recurrence in a mouse model of NEPC.
- HOC downregulated neuroendocrine markers SYP and CHGA in treated tumors.

## Abstract

S-(-)-Hydroxyoleocanthal (HOC, oleacein), a natural phenolic derived from extra-virgin olive oil, demonstrates potent inhibitory effects against neuroendocrine prostate cancer (NEPC), the most aggressive subtype of prostate cancer (PCa). Daily oral administration of HOC in a nude mouse NEPC xenograft model markedly suppressed the tumor expression of EPHA3 and BRN2, along with their downstream effectors EZH2, ASCL1, and DLL3 and neuroendocrine markers SYP and CHGA. Disruption of this signaling axis impaired NEPC progression and recurrence. These findings suggest that HOC targets critical molecular pathways driving PCa lineage plasticity and aggressiveness, supporting its potential as a promising nutraceutical lead candidate for NEPC control.

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.