Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China.
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China.
Free Radic Biol Med. 2023 Aug 20;205:318-331. doi: 10.1016/j.freeradbiomed.2023.06.006. Epub 2023 Jun 22.
Neuroendocrine prostate cancer (NEPC) is a multi-resistant variant of prostate cancer (PCa) that frequently emerges in castration-resistant prostate cancer (CRPC). NEPC is usually associated with tumor aggression, hormone therapy resistance, and poor clinical outcome. However, the mechanisms underlying the trans-differentiation from CRPC to NEPC have not been elucidated. Achaete-scute complex-like 1 (ASCL1) plays a role in neuronal commitment and differentiation and olfactory and autonomic neuron generation. This study revealed that ASCL1 was regulated by the SRY-box transcription factor 2 (SOX2) and highly expressed in NEPC cells, which was closely related to poor prognosis. Moreover, ASCL1 overexpression significantly enhanced CRPC progression to NEPC by resisting ferroptosis. Mechanically, ferroptosis resistance was mediated by CAMP-responsive element binding protein 1 (CREB1) phosphorylation, promoted by substantially upregulated ASCL1 in NEPC cells. In addition, upregulated SOX2 induced PCa cell differentiation into neuroendocrine tumors by mediating their lineage changes. In conclusion, inhibiting the ferroptosis resistance mediated by ASCL1 could provide a new NEPC therapeutic target and increase patient survival.
神经内分泌前列腺癌（NEPC）是一种对前列腺癌（PCa）具有多抗性的变体，通常在去势抵抗性前列腺癌（CRPC）中出现。NEPC 通常与肿瘤侵袭性、激素治疗耐药性和不良临床结局相关。然而，从 CRPC 向 NEPC 转化的机制尚未阐明。achaete-scute complex-like 1（ASCL1）在神经元的承诺和分化以及嗅觉和自主神经元的产生中发挥作用。本研究表明，ASCL1 受性别决定区 Y 框转录因子 2（SOX2）调控，在 NEPC 细胞中高表达，与预后不良密切相关。此外，ASCL1 的过表达通过抵抗铁死亡显著增强了 CRPC 向 NEPC 的进展。在机制上，铁死亡抵抗是由 CAMP 反应元件结合蛋白 1（CREB1）磷酸化介导的，这在 NEPC 细胞中被大量上调的 ASCL1 所促进。此外，上调的 SOX2 通过介导其谱系变化将 PCa 细胞分化为神经内分泌肿瘤。总之，抑制 ASCL1 介导的铁死亡抵抗可能为 NEPC 提供新的治疗靶点并提高患者生存率。
