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 phenolicS-(-)-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.
背景/目的。前列腺癌是美国男性癌症相关死亡的第二大原因。使用第二代雄激素受体抑制剂（如恩杂鲁胺）治疗可引发谱系可塑性，促使前列腺癌细胞转分化为不依赖雄激素受体、低分化的神经内分泌表型。受体酪氨酸激酶EPHA3是驱动神经内分泌前列腺癌的关键因子，在前列腺癌中过度表达，尤其在雄激素非依赖型和神经内分泌亚型中。EPHA3通过激活c-Myc信号通路增强EZH2表达，促进组蛋白H3K27三甲基化。神经转录因子BRN2作用于EZH2和ASCL1上游，而ASCL1调控Notch通路配体DLL3，从而协调神经内分泌分化。经典神经内分泌标志物CHGA和SYP表达升高是神经内分泌前列腺癌表型的特征。本研究报道了橄榄酚类化合物S-(-)-羟基油橄榄苦素通过靶向EPHA3–BRN2–EZH2–ASCL1–DLL3–SYP–CHGA致癌网络，有效控制神经内分泌前列腺癌的新用途。 方法。通过细胞活力实验评估体外效应。为模拟神经内分泌前列腺癌进展与复发，将NCI-H660-Luc细胞异种移植至雄性无胸腺裸鼠体内。通过RNA测序比较安慰剂对照组与治疗组肿瘤的差异表达基因。 结果。S-(-)-羟基油橄榄苦素在体外显著抑制神经内分泌前列腺癌NCI-H660细胞增殖。每日以10毫克/千克体重的剂量口服给药，能明显抑制NCI-H660-Luc肿瘤进展。在原发肿瘤手术切除后持续给药，可大幅降低局部复发率。与安慰剂对照组相比，治疗组原发及复发肿瘤中EPHA3、BRN2、EZH2、ASCL1、DLL3、SYP和CHGA的表达均显著下调。 结论。这些研究结果证实S-(-)-羟基油橄榄苦素作为多靶点治疗分子，能够破坏神经内分泌前列腺癌关键致癌网络，凸显其作为侵袭性神经内分泌前列腺癌新型先导干预策略的潜力。
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