Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China.
Department of Pathology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China.
Nat Commun. 2023 Nov 28;14(1):7794. doi: 10.1038/s41467-023-43676-3.
Neuroendocrine prostate cancer is a rapidly progressive and lethal disease characterized by early visceral metastasis, poor prognosis, and limited treatment options. Uncovering the oncogenic mechanisms could lead to the discovery of potential therapeutic avenues. Here, we demonstrate that the RNA-binding protein ELAVL3 is specifically upregulated in neuroendocrine prostate cancer and that overexpression of ELAVL3 alone is sufficient to induce the neuroendocrine phenotype in prostate adenocarcinoma. Mechanistically, ELAVL3 is transcriptionally regulated by MYCN and subsequently binds to and stabilizes MYCN and RICTOR mRNA. Moreover, ELAVL3 is shown to be released in extracellular vesicles and induce neuroendocrine differentiation of adenocarcinoma cells via an intercellular mechanism. Pharmacological inhibition of ELAVL3 with pyrvinium pamoate, an FDA-approved drug, effectively suppresses tumor growth, reduces metastatic risk, and improves survival in neuroendocrine prostate cancer mouse models. Our results identify ELAVL3 as a critical regulator of neuroendocrine differentiation in prostate cancer and propose a drug repurposing strategy for targeted therapies.
神经内分泌前列腺癌是一种快速进展和致命的疾病，其特征是早期内脏转移、预后不良和治疗选择有限。揭示致癌机制可能会发现潜在的治疗途径。在这里，我们证明 RNA 结合蛋白 ELAVL3 在神经内分泌前列腺癌中特异性地上调，并且单独过表达 ELAVL3 足以诱导前列腺腺癌的神经内分泌表型。在机制上，ELAVL3 受 MYCN 转录调控，随后与 MYCN 和 RICTOR mRNA 结合并稳定它们。此外，ELAVL3 被证明可以在细胞外囊泡中释放，并通过细胞间机制诱导腺癌细胞的神经内分泌分化。用已批准用于临床的药物吡嗪酰胺抑制 ELAVL3 的表达可有效抑制肿瘤生长、降低转移风险并改善神经内分泌前列腺癌小鼠模型的存活率。我们的研究结果确定 ELAVL3 是前列腺癌神经内分泌分化的关键调节因子，并提出了一种针对该蛋白的药物再利用策略。
