Transcriptome profiling reveals that VNPP433-3β, the lead next-generation galeterone analog inhibits prostate cancer stem cells by downregulating epithelial-mesenchymal transition and stem cell markers.
Transcriptome profiling reveals that VNPP433-3β, the lead next-generation galeterone analog inhibits prostate cancer stem cells by downregulating epithelial-mesenchymal transition and stem cell markers.
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转录组分析显示，下一代加列酮类似物的先导化合物VNPP433 - 3β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。
DOI：
10.1002/mc.23406
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发表时间：
2022-07
影响因子：
4.6
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中科院分区：
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癌症干细胞（CSCs）实际上存在于所有肿瘤中，尽管数量很少，但却是推动癌症进展、转移、耐药和复发的主要原因。前列腺癌（PCa）是全球男性中第二常见的癌症，尽管医学取得了巨大进步，但去势抵抗性前列腺癌（CRPC）仍然是一个重大挑战。目前，现有的治疗方案对治疗CRPC均无效。我们之前报道过，下一代加列酮类似物的先导化合物VNPP433 - 3β对治疗CRPC的临床前体内模型有效。在这项使用RNA测序、细胞学和生化方法的研究中，我们报道VNPP433 - 3β通过靶向对干性和上皮 - 间质转化至关重要的关键通路来抑制前列腺癌症干细胞。VNPP433 - 3β抑制前列腺癌中的癌症干细胞，可能是通过降解雄激素受体（AR），从而减少包括BMI1和KLF4在内的几种干细胞标志物的AR介导的转录。通过RNA测序、 Ingenuity通路分析和基因集富集分析进行的转录组分析表明，VNPP433 - 3β抑制了对前列腺癌症干细胞至关重要的几个基因和功能通路的转录，从而在靶向肿瘤主体的同时抑制了前列腺癌中的癌症干细胞。
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.