雄激素消除疗法可有效抑制雄激素受体 (AR) 阳性 (AR) 前列腺癌 (PCa) 细胞亚型，但会导致 AR 阴性 (AR-) PCa 细胞亚型增加。本研究旨在调查导致细胞类型比例变化的有争议的机制，将 CXCL8 确定为 AR-PCa 细胞的合成重要效应子。研究发现 AR-PCa 细胞容易受到 CXCL8 耗尽或抑制的影响，从而损害其生存。从机制上讲，雄激素消除疗法会抑制 AR 信号传导，从而导致 CXCL8 基因转录上调。 CXCL8 反过来激活 mTORC1 通路，通过激活甾醇调节元件结合蛋白 2 (SREBP2) 增加胆固醇从头合成。总之，这些结果表明，在雄激素消融疗法下，CXCL8-mTORC1-SREBP2 轴导致 AR-PCa 细胞致瘤性加剧。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Treatment with androgen-ablative therapies effectively inhibited androgen receptor (AR)-positive (AR+) prostate cancer (PCa) cell subtypes, but it resulted in an increase in AR-negative (AR-) PCa cell subtypes. The present study aimed to investigate the debated mechanisms responsible for the changing proportion of cell types, identifying CXCL8 as a synthetic essential effector of AR- PCa cells. AR- PCa cells were found to be susceptible to CXCL8 depletion or inhibition, which impaired their survival. Mechanistically, androgen-ablative therapies resulted in the suppression of AR signaling, leading to the upregulation of CXCL8 gene transcription. CXCL8, in turn, activated the mTORC1 pathway, which increased de novo cholesterol synthesis by activating sterol regulatory element-binding protein-2 (SREBP2). Together, these results suggested that the CXCL8-mTORC1-SREBP2 axis contributed to the exacerbation of tumorigenicity in AR- PCa cells under androgen-ablative therapies.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.