抗雄激素和化疗 (Cx) 的耐药性限制了激素敏感型 (mHSPC) 和激素抵抗型前列腺癌 (mCRPC) 患者的治疗选择。在这种情况下，糖皮质激素受体（GR）的上调已被确定为 mCRPC 中的潜在旁路机制，多西他赛和米非司酮（RU-486 博士）（一种 GR 抑制剂）的组合可重新敏化多西他赛耐药细胞模型到 Cx。这项研究旨在阐明造成这种现象的分子机制。在 Doc RU-486 治疗后的多西紫杉醇耐药 PCa 细胞模型中进行 RNA 测序 (RNA-seq) 并进行连续功能测定。所选蛋白质的表达在患有进展性疾病的前列腺癌（PCa）患者的前列腺组织中得到验证。 Doc RU-486 治疗显着降低了癌细胞活力和 RNA-Seq。揭示结合转录因子 1 (SREBF-1) 的甾醇调节元件（胆固醇和脂质生物合成的转录因子）是显着下调的靶标。功能分析证实 SREBF-1 下调是造成这一现象的部分原因。一致地，SREBF-1 敲低和药理学 SREBP 抑制，以及胆固醇途径中的其他关键酶，显示出相似的结果。此外，SREBF-1 表达在晚期 PCa 组织中显着升高，表明其可能参与肿瘤进展和新出现的治疗耐药性。因此，胆固醇和脂质生物合成的特异性抑制也可能针对 Cx 耐药癌细胞，并代表未来改善 mCRPC 治疗的潜在附加治疗选择。版权所有 © 2024。由 Elsevier Inc. 出版。

Resistance to anti-androgens and chemotherapy (Cx) limits therapeutic options for patients with hormone-sensitive (mHSPC) and hormone-resistant prostate cancer (mCRPC). In this context, upregulation of the glucocorticoid receptor (GR) has been identified as a potential bypass mechanism in mCRPC, and a combination of docetaxel and mifepristone (Doc + RU-486), an inhibitor of GR, re-sensitized docetaxel-resistant cell models to Cx. This study was designed to elucidate the molecular mechanisms responsible for this phenomenon. RNA sequencing (RNA-seq) in docetaxel-resistant PCa cell models after Doc + RU-486 treatment with consecutive functional assays were performed. Expression of selected proteins was verified in prostatic tissue from prostate cancer (PCa) patients with progressive disease. Treatment with Doc + RU-486 significantly reduced cancer cell viability and RNA-Seq. revealed sterol regulatory element of binding transcription factor 1 (SREBF-1), a transcription factor of cholesterol and lipid biosynthesis, as a significantly downregulated target. Functional assays confirmed that SREBF-1 downregulation is partially responsible for this observation. In concordance, SREBF-1 knockdown and pharmacological SREBP inhibition, together with other key enzymes in the cholesterol pathway, showed similar results. Furthermore, SREBF-1 expression is significantly elevated in advanced PCa tissues, demonstrating its potential involvement in tumor progression and emerging therapy resistance. Therefore, specific inhibition of cholesterol and lipid biosynthesis might also target Cx-resistant cancer cells and represent a potential additive future therapeutic option to improve mCRPC therapy.Copyright © 2024. Published by Elsevier Inc.