Cancer stem cells (CSCs) virtually present in all tumors albeit in small numbers are primarily responsible for driving cancer progression, metastasis, drug resistance, and recurrence. Prostate cancer (PCa) is the second most frequent cancer in men worldwide, and castration resistant prostate cancer (CRPC) remains a major challenge despite the tremendous advancements in medicine. Currently, none of the available treatment options are effective in treating CRPC. We earlier reported that VNPP433-3β, the lead next-generation galeterone analog is effective in treating preclinical in vivo models of CRPC. In this study using RNA-seq, cytological, and biochemical methods, we report that VNPP433-3β inhibits prostate CSCs by targeting key pathways critical to stemness and epithelial–mesenchymal transition. VNPP433-3β inhibits CSCs in PCa, presumably by degrading the androgen receptor (AR) thereby decreasing the AR-mediated transcription of several stem cell markers including BMI1 and KLF4. Transcriptome analyses by RNA-seq, Ingenuity Pathway Analysis, and Gene Set Enrichment Analysis demonstrate that VNPP433-3β inhibits transcription of several genes and functional pathways critical to the prostate CSCs thereby inhibiting CSCs in PCa besides targeting the bulk of the tumor.

中文翻译：

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转录组分析显示 VNPP433-3β，领先的下一代 galeterone 类似物通过下调上皮-间质转化和干细胞标志物来抑制前列腺癌干细胞

癌症干细胞 (CSC) 实际上存在于所有肿瘤中，尽管数量很少，但它们主要负责推动癌症进展、转移、耐药性和复发。前列腺癌 (PCa) 是全球男性第二常见的癌症，尽管医学取得了巨大进步，但去势抵抗性前列腺癌 (CRPC) 仍然是一项重大挑战。目前，没有一种可用的治疗方案对治疗 CRPC 有效。我们早先报道了 VNPP433-3β，领先的下一代 galeterone 类似物在体内治疗临床前有效CRPC 模型。在这项使用 RNA-seq、细胞学和生化方法的研究中，我们报告 VNPP433-3β 通过靶向对干性和上皮-间质转化至关重要的关键途径来抑制前列腺 CSC。VNPP433-3β 抑制 PCa 中的 CSC，可能是通过降解雄激素受体 (AR) 从而降低 AR 介导的几种干细胞标志物的转录，包括 BMI1 和 KLF4。通过 RNA-seq、Ingenuity Pathway 分析和基因集富集分析进行的转录组分析表明，VNPP433-3β 抑制了对前列腺 CSC 至关重要的几个基因和功能通路的转录，从而抑制了 PCa 中的 CSC，除了靶向肿瘤的大部分。