去势抗性前列腺癌（CRPC）是一种对雄激素剥夺治疗（ADT）具有抵抗性的晚期癌症。由于CRPC的治疗反应差，迫切需要新的治疗策略。本研究旨在澄清SOX2 / Notch轴在CRPC中的调节作用。为了评估前列腺癌（PCa）和CRPC组织中SOX2，Notch和Hey1的表达，我们进行了免疫组化（IHC）分析。通过RT-PCR，蛋白质印迹和免疫荧光，评估了恩扎鲁胺耐药性LNCaP细胞（Enza-R）中SOX2和Notch的表达。我们使用CCK-8，Transwell，创伤愈合和蛋白质印迹分析来评估Enza-R细胞的存活能力，侵袭性，迁移性，细胞周期和耐药性。与PCa组织相比，CRPC组织表达SOX2，Notch1和Hey1明显增加。SOX2阳性患者更容易发展骨转移。在Enza-R细胞中检测到与SOX2和Notch相关的信号的显著激活。明显抑制SOX2可以明显关闭Notch信号并抑制Enza-R细胞的恶性行为，包括增殖，侵袭，迁移和耐药性。γ-分泌酶抑制剂GSI-IX通过抑制体外中Notch信号阻断了恩扎鲁胺耐药性。此外，GSI-IX单独对Enza-R细胞具有显著的抗肿瘤作用。我们证明了SOX2 / Notch信号通路在CRPC中对恩扎鲁胺的抵抗性起到了影响。靶向SOX2 / Notch信号通路可能成为CRPC的一种新选择治疗方法。© 2023年，作者，独家许可给Springer Nature B.V.

Castration-resistant prostate cancer (CRPC) is a terminal type of advanced cancer resistant to androgen deprivation therapy (ADT). Due to the poor therapeutic response of CRPC, novel treatment strategies are urgently required. This study aimed to clarify the regulatory roles of the SOX2/Notch axis in CRPC.For the evaluation of the SOX2, Notch, and Hey1 expression in the prostate cancer (PCa) and CRPC tissues, we conducted immunohistochemistry (IHC) analyses. RT-PCR, Western blotting, and immunofluorescence were performed to evaluate SOX2 and Notch expression in enzalutamide-resistant LNCaP cells (Enza-R). CCK-8, Transwell, Wound healing, and Western blotting assays were used to assess the viability, invasion, migration, cell cycle, and drug-resistant in Enza-R cells.Compared to the PCa tissues, CRPC tissues exhibited significantly elevated SOX2, Notch1, and Hey1 expression. SOX2-positive patients were more likely to develop bone metastases than SOX2-negative ones. Significant activation of the signaling associated with SOX2 and Notch was detected in Enza-R cells. The suppression of SOX2 clearly inactivated the Notch signaling and inhibited malignant behaviors, including proliferation, invasion, migration, and drug resistance in Enza-R cells. Theγsecretase inhibitor, GSI-IX, abrogated the enzalutamide resistance by inhibiting Notch signaling in vitro in vitro. Also, GSI-IX alone had a significant anti-tumor effect in Enza-R cells.We demonstrated that SOX2/Notch signaling was responsible for Enzalutamide resistance in CRPC. Targeting SOX2/Notch signaling might represent a new choice for the treatment and therapy of CRPC.© 2023. The Author(s), under exclusive licence to Springer Nature B.V.