Normalization of Enzyme Expression and Activity Regulating Vitamin A Metabolism Increases RAR-Beta Expression and Reduces Cellular Migration and Proliferation in Diseases Caused by Tuberous Sclerosis Gene Mutations.
Normalization of Enzyme Expression and Activity Regulating Vitamin A Metabolism Increases RAR-Beta Expression and Reduces Cellular Migration and Proliferation in Diseases Caused by Tuberous Sclerosis Gene Mutations.
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调节维生素A代谢的酶的表达和活性的正常化增加了RAR-Beta的表达，并减少了由结节性硬化症基因突变引起的疾病中的细胞迁移和增殖。
DOI：
10.3389/fonc.2021.644592
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发表时间：
2021
影响因子：
4.7
通讯作者：
Pongracz JE
中科院分区：
文献类型：
--
作者：
Abdelwahab EMM;Bovari-Biri J;Smuk G;Harko T;Fillinger J;Moldvay J;Krymskaya VP;Pongracz JE
结节性硬化症基因（TSC 1或2）的突变导致雷帕霉素哺乳动物靶标（mTOR）的持续激活。mTOR活化改变细胞，包括维生素A代谢和视黄酸受体β（RARβ）表达。本研究的目的是探讨维生素A代谢和TSC突变之间的分子联系。我们还旨在研究FDA批准的药物雷帕霉素和维生素A代谢产物维甲酸（RA）在TSC突变细胞系中的作用。在人肾血管平滑肌脂肪瘤衍生的细胞系、原发性淋巴管平滑肌瘤病（LAM）组织衍生的LAM细胞系中评估维生素A相关代谢酶和RARβ的表达和活性。还在原发性LAM肺组织切片中测试RARβ蛋白水平。进行TaqMan阵列、酶活性、qRT-PCR、免疫组织化学、免疫荧光染色和蛋白质印迹分析。在划痕和BrDU测定中测试视黄酸（RA）和雷帕霉素的功能作用以评估细胞迁移和增殖。代谢酶阵列显示，参与维生素A代谢的许多酶，包括乙醛脱氢酶（ALDHs），乙醇脱氢酶（ADH）和细胞色素P450 2 E1（CYP 2 E1）的普遍失调。此外，RARβ下调是所有TSC缺陷细胞系和原代组织的特征。两种FDA批准的药物-用于急性髓性白血病的RA和用于TSC突变的雷帕霉素-的组合使ALDH和ADH表达和活性正常化，恢复RARβ表达并减少细胞增殖和迁移。维生素A代谢酶的失调是TSC突变的特征。RA可以使RARβ水平正常化并限制细胞迁移，但对增殖没有显著影响。基于我们的数据，翻译研究可以证实RA与减少剂量的雷帕霉素的组合是否会比更高剂量的雷帕霉素单药治疗更有益，同时减少雷帕霉素对TSC突变患者的不良反应。
Mutation in a tuberous sclerosis gene (TSC1 or 2) leads to continuous activation of the mammalian target of rapamycin (mTOR). mTOR activation alters cellular including vitamin A metabolism and retinoic acid receptor beta (RARβ) expression. The goal of the present study was to investigate the molecular connection between vitamin A metabolism and TSC mutation. We also aimed to investigate the effect of the FDA approved drug rapamycin and the vitamin A metabolite retinoic acid (RA) in cell lines with TSC mutation. Expression and activity of vitamin A associated metabolic enzymes and RARβ were assessed in human kidney angiomyolipoma derived cell lines, primary lymphangioleiomyomatosis (LAM) tissue derived LAM cell lines. RARβ protein levels were also tested in primary LAM lung tissue sections. TaqMan arrays, enzyme activities, qRT-PCRs, immunohistochemistry, immunofluorescent staining, and western blotting were performed and analysed. The functional effects of retinoic acid (RA) and rapamycin were tested in a scratch and a BrDU assay to assess cell migration and proliferation. Metabolic enzyme arrays revealed a general deregulation of many enzymes involved in vitamin A metabolism including aldehyde dehydrogenases (ALDHs), alcohol dehydrogenases (ADHs) and Cytochrome P450 2E1 (CYP2E1). Furthermore, RARβ downregulation was a characteristic feature of all TSC-deficient cell lines and primary tissues. Combination of the two FDA approved drugs -RA for acute myeloid leukaemia and rapamycin for TSC mutation- normalised ALDH and ADH expression and activity, restored RARβ expression and reduced cellular proliferation and migration. Deregulation of vitamin A metabolizing enzymes is a feature of TSC mutation. RA can normalize RARβ levels and limit cell migration but does not have a significant effect on proliferation. Based on our data, translational studies could confirm whether combination of RA with reduced dosage of rapamycin would have more beneficial effects to higher dosage of rapamycin monotherapy meanwhile reducing adverse effects of rapamycin for patients with TSC mutation.
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影响因子：
5.3
作者：
Flamini MI;Gauna GV;Sottile ML;Nadin BS;Sanchez AM;Vargas-Roig LM
通讯作者：
Vargas-Roig LM
影响因子：
5.9
作者：
Chelstowska S;Widjaja-Adhi MA;Silvaroli JA;Golczak M
通讯作者：
Golczak M
影响因子：
3.4
作者：
Cheung, Yuen-Ting;Lau, Way Kwok-Wai;Chang, Raymond Chuen-Chung
通讯作者：
Chang, Raymond Chuen-Chung
影响因子：
8
作者：
Li, Yang;Wongsiriroj, Nuttaporn;Blaner, William S
通讯作者：
Blaner, William S
DOI：
10.1165/rcmb.2012-0476oc
发表时间：
2013-07-01
影响因子：
6.4
作者：
Li, Chenggang;Zhou, Xiaobo;Yu, Jane J.
通讯作者：
Yu, Jane J.