Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China.
Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China; Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China.
Cell Signal. 2022 Jul;95:110336. doi: 10.1016/j.cellsig.2022.110336. Epub 2022 Apr 20.
The intratumoral androgen synthesis is one of the mechanisms by which androgen receptor (AR) is aberrantly re-activated in castration-resistant prostate cancer (CRPC) after androgen ablation. However, pathways controlling steroidogenic enzyme expression and de novo androgen synthesis in prostate cancer (PCa) cells are largely unknown. In this study, we explored the potential roles of DAB2IP in testosterone synthesis and CRPC tumor growth. Indeed, DAB2IP loss could maintain AR transcriptional activity, PSA re-expression and tumor growth under castrated condition in vitro and in vivo, and reprogram the expression profiles of steroidogenic enzymes, including AKR1C3. Mechanistically, DAB2IP could dramatically inhibit the AKR1C3 promoter activity and the conversion from androgen precursors (i.e., DHEA) to testosterone through PI3K/AKT/mTOR/ETS1 signaling. Consistently, there was a high co-expression of ETS1 and AKR1C3 in PCa tissues and xenografts, and their expression in prostate tissues could also restore AR nuclear staining in castrated DAB2IP-/- mice after DHEA supplement. Together, this study reveals a novel regulation of intratumoral de novo androgen synthesis in CRPC, and provides the DAB2IP/ETS1/AKR1C3 signaling as a potential therapeutic target.
肿瘤内雄激素合成是去势抵抗性前列腺癌（CRPC）中雄激素受体（AR）异常激活的机制之一，在去势后。然而，前列腺癌（PCa）细胞中控制甾体生成酶表达和从头合成雄激素的途径在很大程度上尚不清楚。在这项研究中，我们探讨了 DAB2IP 在睾酮合成和 CRPC 肿瘤生长中的潜在作用。事实上，DAB2IP 缺失可以维持 AR 的转录活性、PSA 的重新表达和体内外去势条件下的肿瘤生长，并重新编程甾体生成酶的表达谱，包括 AKR1C3。在机制上，DAB2IP 可以通过 PI3K/AKT/mTOR/ETS1 信号显著抑制 AKR1C3 启动子活性和从雄激素前体（即 DHEA）向睾酮的转化。一致地，在 PCa 组织和异种移植物中，ETS1 和 AKR1C3 高度共表达，并且在前列腺组织中，它们的表达也可以在 DHEA 补充后恢复去势 DAB2IP-/- 小鼠中 AR 的核染色。总之，这项研究揭示了 CRPC 中肿瘤内从头合成雄激素的新调控机制，并提供了 DAB2IP/ETS1/AKR1C3 信号作为潜在的治疗靶点。
