Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China.
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, SC, China.
Oncogene. 2024 Nov;43(47):3456-3468. doi: 10.1038/s41388-024-03181-3. Epub 2024 Oct 5.
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.
雄激素剥夺疗法有效地抑制了雄激素受体（AR）阳性（AR+）前列腺癌（PCa）细胞亚型，但导致 AR 阴性（AR-）PCa 细胞亚型的增加。本研究旨在探讨导致细胞类型比例变化的有争议的机制，确定 CXCL8 是 AR- PCa 细胞的合成必需效应物。研究发现 AR- PCa 细胞易受 CXCL8 耗竭或抑制的影响，这会损害它们的存活。从机制上讲，雄激素剥夺疗法导致 AR 信号的抑制，导致 CXCL8 基因转录的上调。CXCL8 反过来激活了 mTORC1 通路，通过激活固醇调节元件结合蛋白-2（SREBP2）来增加从头胆固醇合成。总之，这些结果表明，在雄激素剥夺疗法下，CXCL8-mTORC1-SREBP2 轴导致 AR- PCa 细胞的致瘤性恶化。
