School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas.
Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
Cancer Prev Res (Phila). 2021 Jun;14(6):635-648. doi: 10.1158/1940-6207.CAPR-20-0589. Epub 2021 Mar 1.
We reported efficacy of Nakai (AGN) root ethanol extract and equimolar decursin (D)/decursinol angelate (DA) through daily gavage starting at 8 weeks of age (WOA) to male transgenic adenocarcinoma of mouse prostate (TRAMP) mice such that these modalities suppressed precancerous epithelial lesions in their dorsolateral prostate (DLP) to similar extent, but AGN extract was better than the D/DA mixture at promoting the survival of mice bearing prostate neuroendocrine carcinomas to 28 WOA. Here, we compared by microarray hybridization the mRNA levels in pooled DLP tissues and individual neuroendocrine carcinomas to characterize potential molecular targets of AGN extract and D/DA. Clustering and principal component analyses supported distinct gene expression profiles of TRAMP DLP versus neuroendocrine carcinomas. Pathway Enrichment, Gene Ontology, and Ingenuity Pathway Analyses of differential genes indicated that AGN and D/DA affected chiefly processes of lipid and mitochondrial energy metabolism and oxidation-reduction in TRAMP DLP, while AGN affected neuronal signaling, immune systems and cell cycling in neuroendocrine carcinomas. Protein-Protein Interaction Network analysis predicted and reverse transcription-PCR verified multiple hub genes common in the DLP of AGN- and D/DA-treated TRAMP mice at 28 WOA and select hub genes attributable to the non-D/DA AGN components. The vast majority of hub genes in the AGN-treated neuroendocrine carcinomas differed from those in TRAMP DLP. In summary, the transcriptomic approach illuminated vastly different signaling pathways and networks, cellular processes, and hub genes of two TRAMP prostate malignancy lineages and their associations with the interception efficacy of AGN and D/DA. PREVENTION RELEVANCE: This study explores potential molecular targets associated with activity of AGN root alcoholic extract and its major pyranocoumarins to intercept precancerous epithelial lesions and early malignancies of the prostate. Without an ethically-acceptable, clearly defined cancer initiation risk reduction strategy available for the prostate, using natural products like AGN to delay formation of malignant tumors could be a plausible approach for prostate cancer prevention.
我们报道了从 8 周龄（WOA）开始通过每日灌胃给予中井（AGN）根乙醇提取物和等摩尔量的去芹素（D）/当归酰基去芹醇（DA）对雄性转基因腺癌小鼠前列腺（TRAMP）的疗效，结果表明这些方法在抑制其背外侧前列腺（DLP）的癌前上皮病变方面具有相似的效果，但 AGN 提取物在促进携带前列腺神经内分泌癌的小鼠存活方面优于 D/DA 混合物至 28 WOA。在这里，我们通过微阵列杂交比较了汇集的 DLP 组织和单个神经内分泌癌中的 mRNA 水平，以表征 AGN 提取物和 D/DA 的潜在分子靶标。聚类和主成分分析支持 TRAMP DLP 与神经内分泌癌之间存在明显不同的基因表达谱。差异基因的通路富集、基因本体论和 Ingenuity 通路分析表明，AGN 和 D/DA 主要影响 TRAMP DLP 中的脂质和线粒体能量代谢以及氧化还原过程，而 AGN 影响神经内分泌癌中的神经元信号转导、免疫系统和细胞周期。蛋白质-蛋白质相互作用网络分析预测并经逆转录-PCR 验证了在 28 WOA 时用 AGN 和 D/DA 处理的 TRAMP 小鼠的 DLP 中常见的多个枢纽基因，以及归因于非 D/DA AGN 成分的选择枢纽基因。在 AGN 处理的神经内分泌癌中，绝大多数枢纽基因与 TRAMP DLP 中的基因不同。总之，转录组学方法阐明了两种 TRAMP 前列腺恶性肿瘤谱系及其与 AGN 和 D/DA 阻断疗效相关的信号通路和网络、细胞过程和枢纽基因的巨大差异。预防相关性：本研究探讨了与 AGN 根酒精提取物及其主要吡喃香豆素拦截前列腺癌前上皮病变和早期恶性肿瘤的活性相关的潜在分子靶标。由于没有一种符合伦理道德、明确界定的降低前列腺癌起始风险的策略，因此使用 AGN 等天然产物来延迟恶性肿瘤的形成可能是一种可行的前列腺癌预防方法。
