Androgen receptor (AR) splice variant 7 (AR-V7) is capable to enter nucleus and activate downstream signaling without ligand. AR-V7 assists the tumor growth, cancer metastasis, cancer stemness, and the evolvement of therapy-resistant prostate cancer (PCa). We discovered that caffeic acid phenethyl ester (CAPE) can repress the expression and downstream signaling of AR-V7 in PCa cells. CAPE blocked the gene transcription, nuclear localization, and protein abundance of AR-V7. CAPE inhibited the expression of U2AF65, SF2 and hnRNPF, which were splicing factors for AR-V7 intron. Additionally, CAPE decreased protein stability of AR-V7 and enhanced the proteosome-degradation of AR-V7. We observed that CDK1 and AKT regulated the expression and stability of AR-V7 via phosphorylation of Ser81 and Ser213, respectively. CAPE decreased the expression of CDK1 and AKT. Overexpression of CDK1 restored the abundance of AR-V7 in CAPE-treated PCa cells. Overexpression of AR-V7, AKT or CDK1 rescued the proliferation of PCa cells under CAPE treatment. Intraperitoneal injection of 10 mg/kg CAPE retarded the growth of 22Rv1 xenografts in nude mice and suppressed the protein levels of AR-V7, CDK1 and AKT in 22Rv1 xenografts. Our study provided the rationale of applying CAPE for inhibition of AR-V7 in prostate tumors.

雄激素受体 (AR) 剪接变体 7 (AR-V7) 无需配体即可进入细胞核并激活下游信号传导。AR-V7 有助于肿瘤生长、癌症转移、癌症干细胞和耐药性前列腺癌 (PCa) 的发展。我们发现咖啡酸苯乙酯 (CAPE) 可以抑制 PCa 细胞中 AR-V7 的表达和下游信号传导。CAPE 阻断 AR-V7 的基因转录、核定位和蛋白质丰度。CAPE 抑制 U2AF65、SF2 和 hnRNPF 的表达，这些都是 AR-V7 内含子的剪接因子。此外，CAPE 降低了 AR-V7 的蛋白质稳定性并增强了 AR-V7 的蛋白酶体降解。我们观察到 CDK1 和 AKT 分别通过 Ser81 和 Ser213 的磷酸化调节 AR-V7 的表达和稳定性。CAPE 降低 CDK1 和 AKT 的表达。CDK1 的过表达恢复了 CAPE 处理的 PCa 细胞中 AR-V7 的丰度。AR-V7、AKT 或 CDK1 的过度表达可挽救 CAPE 治疗下 PCa 细胞的增殖。腹腔注射10 mg/kg CAPE可延缓裸鼠22Rv1异种移植物的生长，并抑制22Rv1异种移植物中AR-V7、CDK1和AKT的蛋白水平。我们的研究提供了应用 CAPE 抑制前列腺肿瘤中 AR-V7 的基本原理。