Department of Bioengineering, Marmara University, Istanbul, Turkey.
Department of Biochemistry, Faculty of Medicine, Marmara University, Istanbul, Turkey.
Neuroendocrinology. 2022;112(2):161-173. doi: 10.1159/000515801. Epub 2021 Mar 11.
Prolactinomas, also called lactotroph adenomas, are the most encountered type of hormone-secreting pituitary neuroendocrine tumors in the clinic. The preferred first-line therapy is a medical treatment with dopamine agonists (DAs), 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.
Since the amalgamation of clinical and laboratory data besides tumor histopathogenesis and transcriptional regulatory features of the tumor emerges 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.
We identified 8 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 repurposed drugs including 5-fluorocytosine, 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 the PI3K/Akt signaling pathway and cell cycle arrest via flow cytometry and Western blotting.
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 the 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.
催乳素瘤，也称为催乳素细胞瘤，是临床上最常见的激素分泌性垂体神经内分泌肿瘤。首选的一线治疗方法是使用多巴胺激动剂（DA）进行药物治疗，主要是卡麦角林，以降低血清催乳素水平、肿瘤体积和肿块效应。然而，在某些情况下，患者表现出多巴胺抵抗，肿瘤具有侵袭性行为，或在停药后复发。此外，目前使用的治疗方法有明显的副作用，会损害患者的生活质量。
由于临床和实验室数据的结合，除了肿瘤组织病理学和肿瘤转录调控特征，在催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，利用疾病特异性特征，以及生物和药理学数据，阐明了催乳素瘤中途径和药物的合理优先级。
我们通过基于 mRNA-miRNA 水平数据整合的药物再利用，确定了 8 种候选药物，并通过在 MMQ 细胞系中的体外检测评估了它们的潜力。7 种再利用药物，包括 5-氟胞嘧啶、去甲替林、奈拉替尼、嘌呤霉素、紫杉叶醇、伏立诺他和齐留通，被提议作为治疗催乳素瘤的潜在候选药物。我们通过分析 PI3K/Akt 信号通路和通过流式细胞术和 Western blot 进行细胞周期停滞，进一步假设了药物对 MMQ 细胞活力的可能作用机制。
我们通过 miRNA 和 mRNA 水平数据的整合，展示了催乳素瘤的转录组景观，并基于该整合提出了再利用药物候选物。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。所有药物对细胞周期阶段的影响和对 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 介导的再利用药物治疗催乳素瘤的研究。
