Introduction: Prolactinomas, also called lactotroph adenomas, are the most encountered type of hormone-secreting pituitary neuroendocrine tumors (PitNET) in the clinic. The preferred first-line therapy is a medical treatment with dopamine agonists (DA), mainly cabergoline, to reduce serum prolactin levels, tumor volume, and mass effect. However, in some cases, patients have displayed DA-resistance with aggressive tumor behavior or are faced with recurrence after drug withdrawal. Also, currently used therapeutics have notorious side effects and impair the life quality of the patients. Methods: Since the amalgamation of clinical and laboratory data besides tumor histopathogenesis and transcriptional regulatory features of the tumor emerge to exhibit essential roles in the behavior and progression of prolactinomas, in this work, we integrated mRNA and microRNA (miRNA) level transcriptome data that exploit disease-specific signatures in addition to biological and pharmacological data to elucidate a rational prioritization of pathways and drugs in prolactinoma. Results: We identified eight drug candidates through drug repurposing based on mRNA-miRNA level data integration and evaluated their potential through in vitro assays in the MMQ cell line. Seven re-purposed drugs including 5-flourocytosine, nortriptyline, neratinib, puromycin, taxifolin, vorinostat, and zileuton were proposed as potential drug candidates for the treatment of prolactinoma. We further hypothesized possible mechanisms of drug action on MMQ cell viability through analyzing PI3K/Akt signaling pathway and cell cycle arrest via flow cytometry and western blotting. Discussion: We presented the transcriptomic landscape of prolactinoma through miRNA and mRNA level data integration and proposed repurposed drug candidates based on this integration. We validated our findings through testing cell viability, cell cycle phases, and PI3K/Akt protein expressions. Effects of the drugs on cell cycle phases and inhibition of PI3K/Akt pathway by all drugs gave us promising output for further studies using these drugs in the treatment of prolactinoma. This is the first study that reports miRNA-mediated repurposed drugs for prolactinoma treatment via in vitro experiments.


中文翻译：

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miRNA 介导的药物再利用揭示了用于治疗泌乳素瘤的潜在候选药物

简介：催乳素瘤，也称为催乳素腺瘤，是临床上最常见的分泌激素的垂体神经内分泌肿瘤 (PitNET)。优选的一线治疗是使用多巴胺激动剂 (DA) 药物治疗，主要是卡麦角林，以减少血清催乳素水平、肿瘤体积和占位效应。然而，在某些情况下，患者表现出具有侵袭性肿瘤行为的 DA 抗性或在停药后面临复发。此外，目前使用的疗法具有臭名昭著的副作用并损害患者的生活质量。方法：由于除了肿瘤组织发病机制和肿瘤的转录调控特征外，临床和实验室数据的融合在泌乳素瘤的行为和进展中表现出重要作用，在这项工作中，我们整合了 mRNA 和 microRNA (miRNA) 水平的转录组数据，这些数据利用疾病特异性特征以及生物学和药理学数据来阐明泌乳素瘤中途径和药物的合理优先级。结果：我们通过基于 mRNA-miRNA 水平数据整合的药物再利用确定了八种候选药物，并通过 MMQ 细胞系中的体外测定评估了它们的潜力。包括 5-氟胞嘧啶、去甲替林、来那替尼、嘌呤霉素、紫杉叶素、伏立诺他和齐留通在内的七种重新用途药物被提议作为治疗催乳素瘤的潜在候选药物。我们通过流式细胞术和蛋白质印迹分析 PI3K/Akt 信号通路和细胞周期阻滞，进一步推测了药物对 MMQ 细胞活力的作用机制。讨论：我们通过 miRNA 和 mRNA 水平的数据整合展示了催乳素瘤的转录组学格局，并基于这种整合提出了重新利用的候选药物。我们通过测试细胞活力、细胞周期阶段和 PI3K/Akt 蛋白表达来验证我们的发现。药物对细胞周期阶段的影响和所有药物对 PI3K/Akt 通路的抑制为我们使用这些药物治疗催乳素瘤的进一步研究提供了有希望的结果。这是第一项通过体外实验报告 miRNA 介导的用于泌乳素瘤治疗的再利用药物的研究。药物对细胞周期阶段的影响和所有药物对 PI3K/Akt 通路的抑制为我们使用这些药物治疗催乳素瘤的进一步研究提供了有希望的结果。这是第一项通过体外实验报告 miRNA 介导的用于泌乳素瘤治疗的再利用药物的研究。药物对细胞周期阶段的影响和所有药物对 PI3K/Akt 通路的抑制为我们使用这些药物治疗催乳素瘤的进一步研究提供了有希望的结果。这是第一项通过体外实验报告 miRNA 介导的用于泌乳素瘤治疗的再利用药物的研究。