Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma
Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma
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DOI：
10.1016/j.phrs.2023.106693
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发表时间：
2023-02-14
影响因子：
9.3
通讯作者：
Kajiyama，Hiroaki
中科院分区：
文献类型：
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作者：
Nagao，Yukari;Yokoi，Akira;Kajiyama，Hiroaki
子宫平滑肌肉瘤（ULMS）是一种发生于子宫肌层的恶性间质瘤，预后差，对目前的化疗反应非常有限。本研究旨在通过三步筛选过程，使用由1271种食品和药物管理局批准的药物组成的化学库，确定ULMS的新靶点。首先，我们评估了它们对ULMS细胞的抑制作用，并确定了四种候选物：前海葱苷A、毛花苷C、阿糖胞苷和地高辛。将SK-UT-1细胞皮下或原位移植到小鼠体内建立小鼠肿瘤模型，体内实验结果表明，原海葱素A和毛花苷C具有上级的抗肿瘤作用。mRNA测序结果显示解偶联蛋白2（UCP 2）在sirtuin信号通路中受到抑制，增加活性氧（ROS），诱导细胞死亡。此外，UCP 2的下调诱导ROS和抑制ULMS细胞生长。此外，使用临床样品的分析表明，UCP 2表达在ULMS组织中比在肌瘤组织中在RNA和蛋白质水平均显著上调。这些发现表明，UCP 2是一个潜在的治疗靶点，可以有助于开发ULMS患者的新治疗策略。
Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models.In vivoanalyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS.